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Chen L, Wang X, Wang Y, Yao Q, Liu Y, Zhu Y, Huang H, Yang H, Yang Y, He Y, Qiang L. SQSTM1/p62 Orchestrates Skin Aging via USP7 Degradation. Aging Cell 2025:e70078. [PMID: 40344296 DOI: 10.1111/acel.70078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 03/21/2025] [Accepted: 03/31/2025] [Indexed: 05/11/2025] Open
Abstract
Skin aging is a complex process driven by intrinsic genetic factors and extrinsic environmental influences. In this study, sequestosome1 (SQSTM1/p62) was identified as a key regulator of senescence, the senescence-associated secretory phenotype (SASP), and skin aging. Notably, p62 expression is reduced in senescent cells and aging skin of both humans and mice. The depletion of p62 in the epidermis was found to be positively associated with accelerated aging and the initiation of SASP. Mechanistically, p62 inhibits the accumulation of ubiquitin-specific protease 7 (USP7) during senescence induction by orchestrating its degradation through specific binding interactions. In particular, the Tyr-67 residue within the PB1 domain or Gln-418 within the UBA domain of p62 forms a hydrogen bond with Ala-993 in the Ubl5 domain of USP7. Mutations in either Tyr-67 or Gln-418 of p62, or Ala-993 of USP7, resulted in the induction of cellular senescence, highlighting the critical role of these molecular interactions in the regulation of aging processes.
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Affiliation(s)
- Liu Chen
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaoping Wang
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yuchen Wang
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Qingxin Yao
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Global Platform One Vision, WuXi AppTec, Shanghai, China
| | - Yunyao Liu
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - Yongcheng Zhu
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
| | - He Huang
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Hedan Yang
- Hospital of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Yin Yang
- Hospital of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Yuan He
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Lei Qiang
- State Key Laboratory of Natural Medicines, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China
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Zhang J, Yang W, Zhu Y, Li Z, Zheng Y, Zhang Y, Gao W, Zhang X, Wu Z, Gao L. Microenvironment-induced programmable nanotherapeutics restore mitochondrial dysfunction for the amelioration of non-alcoholic fatty liver disease. Acta Biomater 2025; 194:323-335. [PMID: 39805524 DOI: 10.1016/j.actbio.2025.01.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 01/04/2025] [Accepted: 01/09/2025] [Indexed: 01/16/2025]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a metabolic liver disorder with severe complications. Mitochondrial dysfunction due to over-opening of the mitochondrial permeability transition pore (mPTP) in liver cells plays a central role in the development and progression of NAFLD. Restoring mitochondrial function is a promising strategy for NAFLD therapy. Herein, we designed and developed a microenvironment-induced programmable nanotherapeutic to restore mitochondrial function and ameliorate NAFLD. cyclosporine (Cyclosporine capsules) A (CsA), as a highly effective inhibitors of the opening of mPTP, was chosen in the present work. Nanotherapeutics were prepared by assembling two structurally simple multifunctional glucosamine derivatives: dextran-grafted galactose (Dex-Gal) and Dex-triphenylphosphine (Dex-TPP). Galactose units in the nanotherapeutics guide the hepatocyte-specific uptake. Detachment of galactose from acidic lysosomes via Schiff base cleavage exposes the TPP moieties, which subsequently steers the nanotherapeutics to escape from lysosomes and target mitochondria through an enhanced positive charge, enabling precise in situ drug delivery. Simultaneously, the nanotherapeutics improved mitochondrial dysfunction by inhibiting palmitic acid-induced opening of the mitochondrial permeability transition pore in HepG2 cells, maintaining mitochondrial membrane potential, and decreasing reactive oxygen species production. Furthermore, CsA@Dex-Gal/TPP accumulated in the livers of NAFLD mice, restored mitochondrial autophagy, regulated abnormalities in glucose and lipid metabolism, and improved hepatic lipid deposition. This study offers a new cascading strategy for targeting liver cell mitochondria to treat NAFLD and other mitochondria-associated diseases. STATEMENT OF SIGNIFICANCE: We design microenvironment-induced programmable nanotherapeutics for NAFLD Nanotherapeutics has the capabilities of lysosomal escape and mitochondrial targeting Nanotherapeutics improves mitochondrial dysfunction and ameliorates NAFLD This study offers a new cascading strategy for other mitochondria-associated diseases.
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Affiliation(s)
- Jun Zhang
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Shandong Institute of Endocrine and Metabolic Diseases, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Jinan, Shandong 250012, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
| | - Wenyi Yang
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Shandong Institute of Endocrine and Metabolic Diseases, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Jinan, Shandong 250012, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
| | - Yue Zhu
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Shandong Institute of Endocrine and Metabolic Diseases, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Jinan, Shandong 250012, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
| | - Zhanbin Li
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Shandong Institute of Endocrine and Metabolic Diseases, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Jinan, Shandong 250012, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China
| | - Yin Zheng
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Shandong Institute of Endocrine and Metabolic Diseases, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Jinan, Shandong 250012, China
| | - Yufei Zhang
- Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China
| | - Weisong Gao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Shandong Institute of Endocrine and Metabolic Diseases, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Jinan, Shandong 250012, China
| | - Xinge Zhang
- Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China
| | - Zhongming Wu
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China; Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Shandong Institute of Endocrine and Metabolic Diseases, Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Jinan, Shandong 250012, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
| | - Ling Gao
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education; Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China; Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, Shandong, 250021, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
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Fan Q, Guo G, Hu Y, Lu Y, Su R, Yang J, Xia E, Ma S, Zhang M, Wang J, Li T, Han Y. Hepatic Lamp2a deficiency promotes inflammation of murine autoimmune cholangitis via affecting bile acid metabolism. iScience 2025; 28:111804. [PMID: 39995863 PMCID: PMC11849667 DOI: 10.1016/j.isci.2025.111804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Revised: 10/04/2024] [Accepted: 01/10/2025] [Indexed: 02/26/2025] Open
Abstract
Primary biliary cholangitis is characterized by breaking of immune tolerance and disorders of bile acid metabolism. Our previous study found that abnormal expression of Lamp2 was detected in PBC patients. However, the specific role of Lamp2a in disease progression is still unclear. In this study, we showed that hepatic-specific Lamp2a deficiency could aggravate the inflammatory phenotype of murine autoimmune cholangitis. Mechanistically, the loss of Lamp2a in hepatocytes contributed to the abnormal accumulation of Acot8, thus altered the bile acid components, thereby enhancing the lymphocyte activities, and ultimately promoting the inflammatory phenotype of model mice. Moreover, we also found that Acot8 knockdown could alleviate the liver inflammation caused by Lamp2a deficiency. Altogether, our findings explored the effect of Lamp2a deficiency on the murine autoimmune cholangitis by the perspective of bile acid metabolism, and marked the possibility of Acot8 as a new target for the treatment of PBC disease.
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Affiliation(s)
- Qingling Fan
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi’an 710032, China
| | - Guanya Guo
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi’an 710032, China
| | - Yinan Hu
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi’an 710032, China
| | - Yi Lu
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi’an 710032, China
| | - Rui Su
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi’an 710032, China
| | - Jiaqi Yang
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi’an 710032, China
| | - Erzhuo Xia
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi’an 710032, China
| | - Shuoyi Ma
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi’an 710032, China
| | - Miao Zhang
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi’an 710032, China
| | - Jingbo Wang
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi’an 710032, China
| | - Ting Li
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi’an 710032, China
| | - Ying Han
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Air Force Medical University, Xi’an 710032, China
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Youssef H, Gatto RG, Pham NTT, Jones D, Petersen RC, Machulda MM, Whitwell JL, Josephs KA. Multiple Neuropathologies Underly Hippocampal Subfield Atrophy in a Case With a Slowly Progressive Amnestic Syndrome: Challenging the Notion of Pure LATE-NC. Neuropathology 2025. [PMID: 39973236 DOI: 10.1111/neup.70000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Revised: 02/03/2025] [Accepted: 02/05/2025] [Indexed: 02/21/2025]
Abstract
Alzheimer's disease (AD) is the leading cause of dementia in the elderly, marked by abnormal protein buildup (beta-amyloid and tau) resulting in neuronal loss, especially in the medial temporal lobe and other limbic regions. The presence of transactive response DNA binding protein 43 (TDP-43) immunoreactive inclusions in medial temporal lobe regions has also been associated with neuroimaging changes in limbic regions. It has been proposed that hypometabolism in limbic regions on [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) in a patient with a slowly evolving amnestic syndrome may be a signature of the presence of TDP-43. In this context, we observed an 86-year-old Caucasian female with dementia characterized by a slowly evolving amnestic syndrome, along with focal medial temporal atrophy evident on MRI and hypometabolism in limbic regions on FDG-PET. The patient subsequently died and underwent an autopsy. We performed detailed neuroimaging and digital neuropathological analyses of the hippocampal subfields to better understand the relationship between clinico-imaging findings and histopathology. In addition to TDP-43, we identified three other pathological processes in the medial temporal lobe: sequestosome-1/p62, argyrophilic grain disease (AGD), and primary age-related tauopathy (PART). Hippocampal subfield volumes and rates of atrophy were no different from those of matched healthy controls, except for the atrophy rate in cornu ammonis 1 (CA1). Digital histopathology revealed the relative highest burden of pathology for p62, followed by TDP-43, AGD, and PART in CA1. Multiple pathological processes appear to have contributed to the hippocampal atrophy and hypometabolism in our patient with a slowly progressive amnestic syndrome.
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Affiliation(s)
- Hossam Youssef
- Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
| | - Rodolfo G Gatto
- Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - David Jones
- Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Mary M Machulda
- Department of Psychiatry & Psychology, Mayo Clinic, Rochester, Minnesota, USA
| | | | - Keith A Josephs
- Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA
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5
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de Almeida MMA, De Repentigny Y, Gagnon S, Sutton ER, Kothary R. Impact of liver-specific survival motor neuron (SMN) depletion on central nervous system and peripheral tissue pathology. eLife 2025; 13:RP99141. [PMID: 39976226 PMCID: PMC11841985 DOI: 10.7554/elife.99141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2025] Open
Abstract
Spinal muscular atrophy (SMA) is caused by mutations in the Survival Motor Neuron 1 (SMN1) gene. While traditionally viewed as a motor neuron disorder, there is involvement of various peripheral organs in SMA. Notably, fatty liver has been observed in SMA mouse models and SMA patients. Nevertheless, it remains unclear whether intrinsic depletion of SMN protein in the liver contributes to pathology in the peripheral or central nervous systems. To address this, we developed a mouse model with a liver-specific depletion of SMN by utilizing an Alb-Cre transgene together with one Smn2B allele and one Smn1 exon 7 allele flanked by loxP sites. Initially, we evaluated phenotypic changes in these mice at postnatal day 19 (P19), when the severe model of SMA, the Smn2B/- mice, exhibit many symptoms of the disease. The liver-specific SMN depletion does not induce motor neuron death, neuromuscular pathology or muscle atrophy, characteristics typically observed in the Smn2B/- mouse at P19. However, mild liver steatosis was observed, although no changes in liver function were detected. Notably, pancreatic alterations resembled that of Smn2B/-mice, with a decrease in insulin-producing β-cells and an increase in glucagon-producingα-cells, accompanied by a reduction in blood glucose and an increase in plasma glucagon and glucagon-like peptide (GLP-1). These changes were transient, as mice at P60 exhibited recovery of liver and pancreatic function. While the mosaic pattern of the Cre-mediated excision precludes definitive conclusions regarding the contribution of liver-specific SMN depletion to overall tissue pathology, our findings highlight an intricate connection between liver function and pancreatic abnormalities in SMA.
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Affiliation(s)
- Monique Marylin Alves de Almeida
- Regenerative Medicine Program, Ottawa Hospital Research InstituteOttawaCanada
- Centre for Neuromuscular Disease, University of OttawaOttawaCanada
| | - Yves De Repentigny
- Regenerative Medicine Program, Ottawa Hospital Research InstituteOttawaCanada
| | - Sabrina Gagnon
- Regenerative Medicine Program, Ottawa Hospital Research InstituteOttawaCanada
| | - Emma R Sutton
- Regenerative Medicine Program, Ottawa Hospital Research InstituteOttawaCanada
- Centre for Neuromuscular Disease, University of OttawaOttawaCanada
| | - Rashmi Kothary
- Regenerative Medicine Program, Ottawa Hospital Research InstituteOttawaCanada
- Centre for Neuromuscular Disease, University of OttawaOttawaCanada
- Department of Cellular and Molecular Medicine, University of OttawaOttawaCanada
- Department of Medicine, University of OttawaOttawaCanada
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Hamamoto K, Liang X, Ito A, Lanza M, Bui V, Zhang J, Opozda DM, Hattori T, Chen L, Haddock D, Imamura F, Wang HG, Takahashi Y. Unveiling the physiological impact of ESCRT-dependent autophagosome closure by targeting the VPS37A ubiquitin E2 variant-like domain. Cell Rep 2024; 43:115016. [PMID: 39607828 PMCID: PMC11748760 DOI: 10.1016/j.celrep.2024.115016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 09/05/2024] [Accepted: 11/11/2024] [Indexed: 11/30/2024] Open
Abstract
Macroautophagy (autophagy) involves the formation of phagophores that mature into autophagosomes. The impact of inhibiting autophagosome closure remains unclear. Here, we report the generation and analysis of mice with impaired autophagosome closure by targeting the ubiquitin E2 variant-like (UEVL) β strands of the endosomal sorting complex required for transport (ESCRT) I subunit VPS37A. The VPS37A UEVL mutation (Δ43-139) impairs bulk autophagic flux without disrupting ESCRT-I complex assembly and endosomal function. Homozygous mutant mice exhibit signs of autophagy impairment, including p62/SQSTM1 and ubiquitinated protein accumulation, neuronal dysfunction, growth retardation, antioxidant gene upregulation, and tissue abnormalities. However, about half of the mutant neonates survive to adulthood without severe liver injury. LC3 proximity proteomics reveals that the VPS37A UEVL mutation leads to active TANK-binding kinase 1 (TBK1) accumulation on phagophores, resulting in increased p62 phosphorylation and inclusion formation. These findings reveal a previously unappreciated role of LC3-conjugated phagophores in facilitating protein aggregation and sequestration, potentially alleviating proteotoxicity.
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Affiliation(s)
- Kouta Hamamoto
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Xinwen Liang
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Ayako Ito
- Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Matthew Lanza
- Department of Comparative Medicine, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Van Bui
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Jiawen Zhang
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - David M Opozda
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Tatsuya Hattori
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Longgui Chen
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - David Haddock
- Department of Pathology and Biochemistry, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Fumiaki Imamura
- Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
| | - Hong-Gang Wang
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA; Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
| | - Yoshinori Takahashi
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
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Zhang R, Yang H, Guo M, Niu S, Xue Y. Mitophagy and its regulatory mechanisms in the biological effects of nanomaterials. J Appl Toxicol 2024; 44:1834-1853. [PMID: 38642013 DOI: 10.1002/jat.4609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 03/13/2024] [Accepted: 03/22/2024] [Indexed: 04/22/2024]
Abstract
Mitophagy is a selective cellular process critical for the removal of damaged mitochondria. It is essential in regulating mitochondrial number, ensuring mitochondrial functionality, and maintaining cellular equilibrium, ultimately influencing cell destiny. Numerous pathologies, such as neurodegenerative diseases, cardiovascular disorders, cancers, and various other conditions, are associated with mitochondrial dysfunctions. Thus, a detailed exploration of the regulatory mechanisms of mitophagy is pivotal for enhancing our understanding and for the discovery of novel preventive and therapeutic options for these diseases. Nanomaterials have become integral in biomedicine and various other sectors, offering advanced solutions for medical uses including biological imaging, drug delivery, and disease diagnostics and therapy. Mitophagy is vital in managing the cellular effects elicited by nanomaterials. This review provides a comprehensive analysis of the molecular mechanisms underpinning mitophagy, underscoring its significant influence on the biological responses of cells to nanomaterials. Nanoparticles can initiate mitophagy via various pathways, among which the PINK1-Parkin pathway is critical for cellular defense against nanomaterial-induced damage by promoting mitophagy. The role of mitophagy in biological effects was induced by nanomaterials, which are associated with alterations in Ca2+ levels, the production of reactive oxygen species, endoplasmic reticulum stress, and lysosomal damage.
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Affiliation(s)
- Rui Zhang
- Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, People's Republic of China
| | - Haitao Yang
- Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, People's Republic of China
| | - Menghao Guo
- Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, People's Republic of China
| | - Shuyan Niu
- Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, People's Republic of China
| | - Yuying Xue
- Key Laboratory of Environmental Medicine and Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, People's Republic of China
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García Porta C, Mahfooz K, Komorowska J, Garcia-Rates S, Greenfield S. A Novel 14mer Peptide Inhibits Autophagic Flux via Selective Activation of the mTORC1 Signalling Pathway: Implications for Alzheimer's Disease. Int J Mol Sci 2024; 25:12837. [PMID: 39684549 DOI: 10.3390/ijms252312837] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 11/21/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
During development, a 14mer peptide, T14, modulates cell growth via the α-7 nicotinic acetylcholine receptor (α7 nAChR). However, this process could become excitotoxic in the context of the adult brain, leading to pathologies such as Alzheimer's disease (AD). Recent work shows that T14 acts selectively via the mammalian target of rapamycin complex 1 (mTORC1). This pathway is essential for normal development but is overactive in AD. The triggering of mTORC1 has also been associated with the suppression of autophagy, commonly observed in ageing and neurodegeneration. We therefore investigated the relationship between T14 and autophagic flux in tissue cultures, mouse brain slices, and human Alzheimer's disease hippocampus. Here, we demonstrate that T14 and p-mTOR s2448 expression significantly increases in AD human hippocampus, which was associated with the gradual decrease in the autophagosome number across Braak stages. During development, the reduction in T14 positively correlated with pTau (Ser202, Thr205) and two selective autophagy receptors: p62 and optineurin. In vitro studies also indicated that T14 increases p-mTOR s2448 expression, resulting in the aggregation of polyubiquinated substances. The effective blockade of T14 via its cyclic variant, NBP14, has been validated in vitro, in vivo, and ex vivo. In this study, NBP14 significantly attenuated p-mTOR s2448 expression and restored normal autophagic flux, as seen with rapamycin. We conclude that T14 acts at the α-7 receptor to selectively activate the mTORC1 pathway and consequently inhibit autophagic flux. Hence, this study describes a further step in the process by which T14 could drive neurodegeneration.
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Affiliation(s)
- Cloe García Porta
- Neuro-Bio Ltd., Building F5, Culham Science Centre, Abingdon OX14 3DB, UK
| | - Kashif Mahfooz
- Neuro-Bio Ltd., Building F5, Culham Science Centre, Abingdon OX14 3DB, UK
| | - Joanna Komorowska
- Neuro-Bio Ltd., Building F5, Culham Science Centre, Abingdon OX14 3DB, UK
| | - Sara Garcia-Rates
- Neuro-Bio Ltd., Building F5, Culham Science Centre, Abingdon OX14 3DB, UK
| | - Susan Greenfield
- Neuro-Bio Ltd., Building F5, Culham Science Centre, Abingdon OX14 3DB, UK
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Cominelli G, Lonati C, Pinto D, Rinaldi F, Franco C, Favero G, Rezzani R. Melatonin Attenuates Ferritinophagy/Ferroptosis by Acting on Autophagy in the Liver of an Autistic Mouse Model BTBR T +Itpr3 tf/J. Int J Mol Sci 2024; 25:12598. [PMID: 39684310 DOI: 10.3390/ijms252312598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 11/20/2024] [Accepted: 11/21/2024] [Indexed: 12/18/2024] Open
Abstract
Autism spectrum disorders (ASDs) are a pool of neurodevelopment disorders in which social impairment is the main symptom. Presently, there are no definitive medications to cure the symptoms but the therapeutic strategies that are taken ameliorate them. The purpose of this study was to investigate the effects of melatonin (MLT) in treating ASDs using an autistic mouse model BTBR T+Itpr3tf/J (BTBR). We evaluated the hepatic cytoarchitecture and some markers of autophagy, ferritinophagy/ferroptosis, in BTBR mice treated and not-treated with MLT. The hepatic morphology and the autophagy and ferritinophagy/ferroptosis pathways were analyzed by histological, immunohistochemical, and Western blotting techniques. We studied p62 and microtubule-associated protein 1 light chain 3 B (LC3B) for evaluating the autophagy; nuclear receptor co-activator 4 (NCOA4) and long-chain-coenzyme synthase (ACSL4) for monitoring ferritinophagy/ferroptosis. The liver of BTBR mice revealed that the hepatocytes showed many cytoplasmic inclusions recognized as Mallory-Denk bodies (MDBs); the expression and levels of p62 and LC3B were downregulated, whereas ACSL4 and NCOA4 were upregulated, as compared to control animals. MLT administration to BTBR mice ameliorated liver damage and reduced the impairment of autophagy and ferritinophagy/ferroptosis. In conclusion, we observed that MLT alleviates liver damage in BTBR mice by improving the degradation of intracellular MDBs, promoting autophagy, and suppressing ferritinophagy/ferroptosis.
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Affiliation(s)
- Giorgia Cominelli
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy
| | - Claudio Lonati
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy
- Italian Society for the Study of Orofacial Pain (Società Italiana Studio Dolore Orofacciale-SISDO), 25123 Brescia, Italy
| | - Daniela Pinto
- Human Microbiome Advanced Project Institute, 20129 Milan, Italy
- Interdepartmental University Center of Research Adaption and Regeneration of Tissues and Organs-(ARTO), University of Brescia, 25123 Brescia, Italy
| | - Fabio Rinaldi
- Human Microbiome Advanced Project Institute, 20129 Milan, Italy
- Interdepartmental University Center of Research Adaption and Regeneration of Tissues and Organs-(ARTO), University of Brescia, 25123 Brescia, Italy
| | - Caterina Franco
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy
| | - Gaia Favero
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy
- Interdepartmental University Center of Research Adaption and Regeneration of Tissues and Organs-(ARTO), University of Brescia, 25123 Brescia, Italy
| | - Rita Rezzani
- Anatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy
- Italian Society for the Study of Orofacial Pain (Società Italiana Studio Dolore Orofacciale-SISDO), 25123 Brescia, Italy
- Interdepartmental University Center of Research Adaption and Regeneration of Tissues and Organs-(ARTO), University of Brescia, 25123 Brescia, Italy
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10
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Liu X, Wang J, Yang Z, Xie Q, Diao X, Yao X, Huang S, Chen R, Zhao Y, Li T, Jiang M, Lou Z, Huang C. Upregulated DNMT3a coupling with inhibiting p62-dependent autophagy contributes to NNK tumorigenicity in human bronchial epithelial cells. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2024; 286:117157. [PMID: 39393198 DOI: 10.1016/j.ecoenv.2024.117157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 09/27/2024] [Accepted: 10/04/2024] [Indexed: 10/13/2024]
Abstract
NNK, formally known as 4-(methyl nitrosamine)-1-(3-pyridyl)-1-butanoe, is a potent chemical carcinogen prevalent in cigarette smoke and is a key contributor to the development of human lung adenocarcinomas. On the other hand, autophagy plays a complex role in cancer development, acting as a "double-edged sword" whose impact varies depending on the cancer type and stage. Despite this, the relationship between autophagy and NNK-induced lung carcinogenesis remains largely unexplored. Our current study uncovers a marked reduction in p62 protein expression in both lung adenocarcinomas and lung tissues of mice exposed to cigarette smoke. Interestingly, this reduction appears to be contingent upon the activity of extrahepatic cytochrome P450 (CYP450), revealing that NNK metabolic activation by CYP450 enzyme escalates its potential to induce p62 downregulation. Further mechanistic investigations reveal that NNK suppresses autophagy by accelerating the degradation of p62 mRNA, thereby promoting the malignant transformation of human bronchial epithelial cells. This degradation process is facilitated by the hypermethylation of the Human antigen R (HuR) promoter, resulting in the transcriptional repression of HuR - a key regulator responsible for stabilizing p62 mRNA through direct binding. This hypermethylation is triggered by the activation of ribosomal protein S6, which is influenced by NNK exposure and subsequently amplifies the translation of DNA methyltransferase 3 alpha (DNMT3a). These findings provide crucial insights into the nature of p62 in both the development and potential treatment of tobacco-related lung cancer.
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Affiliation(s)
- Xuelei Liu
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325053, China
| | - Jingjing Wang
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Ziyi Yang
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325053, China
| | - Qipeng Xie
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325053, China; Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China
| | - Xinqi Diao
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325053, China
| | - Xiaoyan Yao
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325053, China
| | - Shirui Huang
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Ruifan Chen
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Yunping Zhao
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325053, China
| | - Tengda Li
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Minghua Jiang
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325053, China; Department of Clinical Laboratory, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.
| | - Zhefeng Lou
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
| | - Chuanshu Huang
- Key Laboratory of Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang 325053, China.
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11
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He L, Kwon D, Trnka MJ, Liu Y, Yang J, Li K, Totah RA, Johnson EF, Burlingame AL, Correia MA. Liver CYP4A autophagic-lysosomal degradation (ALD): A major role for the autophagic receptor SQSTM1/p62 through an uncommon target interaction site. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.14.618315. [PMID: 39464120 PMCID: PMC11507770 DOI: 10.1101/2024.10.14.618315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/29/2024]
Abstract
The hepatic P450 hemoproteins CYPs 4A are typical N-terminally anchored Type I endoplasmic reticulum (ER)-proteins, that are inducible by hypolipidemic drugs and other "peroxisome proliferators". They are engaged in the ω-/ω-1-oxidation of various fatty acids including arachidonic acid, prostaglandins and leukotrienes and in the biotransformation of some therapeutic drugs. Herein we report that of the mammalian liver CYPs 4A, human CYP4A11 and mouse Cyp4a12a are preferential targets of the ER-lysosome-associated degradation (ERLAD). Consequently, these proteins are stabilized both as 1%Triton X100-soluble and -insoluble species in mouse hepatocytes and HepG2-cells deficient in the autophagic initiation ATG5-gene. Although these proteins exhibit surface LC3-interacting regions (LIRs) that would target them directly to the autophagosome, they nevertheless interact intimately with the autophagic receptor SQSTM1/p62. Through structural deletion analyses and site-directed mutagenesis, we have identified the Cyp4A-interacting p62 subdomain to lie between residues 170 and 233, which include its Traf6-binding and LIM-binding subdomains. Mice carrying a liver-specific genetic deletion of p62 residues 69-251 (p62Mut) that includes the CYP4A-interacting subdomain also exhibit Cyp4a-protein stabilization both as Triton X100-soluble and -insoluble species. Consistently, p62Mut mouse liver microsomes exhibit enhanced ω- and ω-1-hydroxylation of arachidonic acid to its physiologically active metabolites 19- and 20-HETEs relative to the corresponding wild-type mouse liver microsomes. Collectively, our findings suggest that any disruption of CYP4A ERLAD results in functionally active P450 protein and consequent production of proinflammatory metabolites on one hand, and insoluble aggregates on the other, which may contribute to pathological aggregates i.e. Mallory-Denk bodies/inclusions, hallmarks of many liver diseases.
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12
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Hinz K, Niu M, Ni HM, Ding WX. Targeting Autophagy for Acetaminophen-Induced Liver Injury: An Update. LIVERS 2024; 4:377-387. [PMID: 39301093 PMCID: PMC11412313 DOI: 10.3390/livers4030027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/22/2024] Open
Abstract
Acetaminophen (APAP) overdose can induce hepatocyte necrosis and acute liver failure in experimental rodents and humans. APAP is mainly metabolized via hepatic cytochrome P450 enzymes to generate the highly reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI), which forms acetaminophen protein adducts (APAP-adducts) and damages mitochondria, triggering necrosis. APAP-adducts and damaged mitochondria can be selectively removed by autophagy. Increasing evidence implies that the activation of autophagy may be beneficial for APAP-induced liver injury (AILI). In this minireview, we briefly summarize recent progress on autophagy, in particular, the pharmacological targeting of SQSTM1/p62 and TFEB in AILI.
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Affiliation(s)
- Kaitlyn Hinz
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Mengwei Niu
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA
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13
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Tang C, Lai Y, Li L, Situ MY, Li S, Cheng B, Chen Y, Lei Z, Ren Y, Zhou J, Wu Y, Zhong H, Li K, Zeng L, Guo Z, Peng S, Huang H. SERPINH1 modulates apoptosis by inhibiting P62 ubiquitination degradation to promote bone metastasis of prostate cancer. iScience 2024; 27:110427. [PMID: 39161960 PMCID: PMC11332800 DOI: 10.1016/j.isci.2024.110427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 04/30/2024] [Accepted: 06/28/2024] [Indexed: 08/21/2024] Open
Abstract
Prostate cancer (PCa) is one of the most prevalent urogenital malignancies. Bone metastasis from PCa reduces patient survival rates significantly. There currently exists no effective treatment for bone metastatic PCa, and the underlying mechanisms remain unclear. This study performed transcriptomic screening on PCa bone metastasis specimens and intersection analysis in public databases and identified SERPINH1 as a potential target for treatment. SERPINH1 was found to be upregulated in PCa bone metastases and with poor prognosis, high Gleason score, and advanced metastatic status. SERPINH1 induced PCa cells' bone metastasis in vivo, promoted their proliferation, and mitigated apoptosis. Mechanistically, SERPINH1 bound to P62, reducing TRIM21-mediated K63-linked ubiquitination degradation of P62 and promoting proliferation and resistance to apoptosis of PCa. This study suggests the regulation of ubiquitination degradation of P62 by SERPINH1 that promotes PCa bone metastasis and can be considered as a potential target for treatment of bone metastatic PCa.
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Affiliation(s)
- Chen Tang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Department of Urology, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, Guangdong 518052, P.R. China
| | - Yiming Lai
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou 510120, Guangdong, P.R. China
- Department of Urology, the Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, P.R. China
| | - Lingfeng Li
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
| | - Min-yi Situ
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, P.R. China
| | - Shurui Li
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
| | - Bisheng Cheng
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
| | - Yongming Chen
- Beijing Hospital, National Center of Gerontology Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, Dongcheng, P.R. China
| | - Zhen Lei
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
| | - YanTing Ren
- Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
| | - Jie Zhou
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
| | - Yongxin Wu
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
| | - Haitao Zhong
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
| | - Kaiwen Li
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou 510120, Guangdong, P.R. China
| | - Lexiang Zeng
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou 510120, Guangdong, P.R. China
| | - Zhenghui Guo
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou 510120, Guangdong, P.R. China
| | - Shengmeng Peng
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou 510120, Guangdong, P.R. China
| | - Hai Huang
- Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong, P.R. China
- Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou 510120, Guangdong, P.R. China
- Department of Urology, the Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, Xinjiang, P.R. China
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14
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Koenig AB, Tan A, Abdelaal H, Monge F, Younossi ZM, Goodman ZD. Review article: Hepatic steatosis and its associations with acute and chronic liver diseases. Aliment Pharmacol Ther 2024; 60:167-200. [PMID: 38845486 DOI: 10.1111/apt.18059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 04/23/2024] [Accepted: 05/13/2024] [Indexed: 06/28/2024]
Abstract
BACKGROUND Hepatic steatosis is a common finding in liver histopathology and the hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), whose global prevalence is rising. AIMS To review the histopathology of hepatic steatosis and its mechanisms of development and to identify common and rare disease associations. METHODS We reviewed literature on the basic science of lipid droplet (LD) biology and clinical research on acute and chronic liver diseases associated with hepatic steatosis using the PubMed database. RESULTS A variety of genetic and environmental factors contribute to the development of chronic hepatic steatosis or steatotic liver disease, which typically appears macrovesicular. Microvesicular steatosis is associated with acute mitochondrial dysfunction and liver failure. Fat metabolic processes in hepatocytes whose dysregulation leads to the development of steatosis include secretion of lipoprotein particles, uptake of remnant lipoprotein particles or free fatty acids from blood, de novo lipogenesis, oxidation of fatty acids, lipolysis and lipophagy. Hepatic insulin resistance is a key feature of MASLD. Seipin is a polyfunctional protein that facilitates LD biogenesis. Assembly of hepatitis C virus takes place on LD surfaces. LDs make important, functional contact with the endoplasmic reticulum and other organelles. CONCLUSIONS Diverse liver pathologies are associated with hepatic steatosis, with MASLD being the most important contributor. The biogenesis and dynamics of LDs in hepatocytes are complex and warrant further investigation. Organellar interfaces permit co-regulation of lipid metabolism to match generation of potentially toxic lipid species with their LD depot storage.
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Affiliation(s)
- Aaron B Koenig
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, USA
| | - Albert Tan
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, USA
- Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia, USA
| | - Hala Abdelaal
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, USA
- Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia, USA
| | - Fanny Monge
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, USA
- Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia, USA
| | - Zobair M Younossi
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, USA
- The Global NASH Council, Center for Outcomes Research in Liver Diseases, Washington, DC, USA
| | - Zachary D Goodman
- Beatty Liver and Obesity Research Program, Inova Health System, Falls Church, Virginia, USA
- Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, Virginia, USA
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15
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Wong MMT, Aziz NA, Ch'ng ES, Armon S, Chook JB, Bong JJ, Peh SC, Wu YS, Teow SY. Expression of LC3A, LC3B and p62/SQSTM1 autophagy proteins in hepatocellular carcinoma (HCC) tissues and the predicted microRNAs involved in the autophagy-related pathway. J Mol Histol 2024; 55:317-328. [PMID: 38630414 DOI: 10.1007/s10735-024-10191-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 03/31/2024] [Indexed: 05/21/2024]
Abstract
BACKGROUND Autophagy plays multifaceted roles in regulating hepatocellular carcinoma (HCC) and the mechanisms involved are under-explored. Regulatory microRNAs (miRNAs) have been reported to target autophagy proteins but their roles in HCC is not well studied. Using HCC patient tissues, this study aims to investigate the association of autophagy with several clinicopathological parameters as well as identifying the autophagy-related miRNAs and the possible pathways. METHODS AND RESULTS Autophagy level in the HCC patient-derived cancer and non-cancer tissues was determined by immunohistochemistry (IHC) targeting SQSTM1, LC3A and LC3B proteins. Significance tests of clinicopathological variables were tested using the Fisher's exact or Chi-square tests. Gene and miRNA expression assays were carried out and analyzed using Nanostring platform and software followed by validation of other online bioinformatics tools, namely String and miRabel. Autophagy expression was significantly higher in cancerous tissues compared to adjacent non-cancer tissues. High LC3B expression was associated with advanced tumor histology grade and tumor location. Nanostring gene expression analysis revealed that SQSTM1, PARP1 and ATG9A genes were upregulated in HCC tissues compared to non-cancer tissues while SIRT1 gene was downregulated. These genes are closely related to an autophagy pathway in HCC. Further, using miRabel tool, three downregulated miRNAs (hsa-miR-16b-5p, hsa-miR-34a-5p, and hsa-miR-660-5p) and one upregulated miRNA (hsa-miR-539-5p) were found to closely interact with the abovementioned autophagy-related genes. We then mapped out the possible pathway involving the genes and miRNAs in HCC tissues. CONCLUSIONS We conclude that autophagy events are more active in HCC tissues compared to the adjacent non-cancer tissues. We also reported the possible role of several miRNAs in regulating autophagy-related genes in the autophagy pathway in HCC. This may contribute to the development of potential therapeutic targets for improving HCC therapy. Future investigations are warranted to validate the target genes reported in this study using a larger sample size and more targeted molecular technique.
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Affiliation(s)
- Magdelyn Mei-Theng Wong
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Jalan University, Bandar Sunway, Selangor Darul Ehsan, Subang Jaya, 47500, Malaysia
| | - Norazlin Abdul Aziz
- Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health (NIH Complex), Ministry of Health Malaysia, Level 4, Block C7, No: 1, Jalan Setia Murni U13/52, Section U13, Setia Alam, Selangor Darul Ehsan, Shah Alam, 40170, Malaysia
| | - Ewe Seng Ch'ng
- Advanced Medical and Dental Institute, University Sains Malaysia, 13200 Kepala Batas, Pulau Pinang, Bertam, Malaysia
| | - Subasri Armon
- Pathology Department, Hospital Kuala Lumpur, Jalan Pahang, Kuala Lumpur, 50588, Malaysia
| | - Jack-Bee Chook
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Jalan University, Bandar Sunway, Selangor Darul Ehsan, Subang Jaya, 47500, Malaysia
| | - Jan-Jin Bong
- Sunway Medical Centre, 5 Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya, 47500, Selangor, Malaysia
| | - Suat-Cheng Peh
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, Jalan University, Bandar Sunway, Selangor Darul Ehsan, Subang Jaya, 47500, Malaysia
- Sunway Medical Centre, 5 Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya, 47500, Selangor, Malaysia
| | - Yuan Seng Wu
- Sunway Microbiome Centre, School of Medical and Life Sciences, Sunway University, Selangor Darul Ehsan, Subang Jaya, 47500, Malaysia
- Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Selangor Darul Ehsan, Subang Jaya, 47500, Malaysia
| | - Sin-Yeang Teow
- Department of Biology, College of Science, Mathematics, and Technology, Wenzhou-Kean University, Daxue Road, Ouhai, Wenzhou, 325060, Zhejiang Province, China.
- Wenzhou Municipal Key Laboratory for Applied Biomedical and Biopharmaceutical Informatics, Ouhai, Wenzhou, 325060, Zhejiang Province, China.
- Zhejiang Bioinformatics International Science and Technology Cooperation Center, Ouhai, Wenzhou, 325060, Zhejiang Province, China.
- Dorothy and George Hennings College of Science, Mathematics and Technology, Kean University, 1000 Morris Ave, Union, NJ, 07083, USA.
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Ortega-Prieto P, Parlati L, Benhamed F, Regnier M, Cavalcante I, Montabord M, Onifarasoaniaina R, Favier M, Pavlovic N, Magusto J, Cauzac M, Pagesy P, Gautheron J, Desdouets C, Guilmeau S, Issad T, Postic C. O-GlcNAc transferase acts as a critical nutritional node for the control of liver homeostasis. JHEP Rep 2024; 6:100878. [PMID: 38298740 PMCID: PMC10827605 DOI: 10.1016/j.jhepr.2023.100878] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 07/06/2023] [Accepted: 07/24/2023] [Indexed: 02/02/2024] Open
Abstract
Background & Aims O-GlcNAcylation is a reversible post-translational modification controlled by the activity of two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). In the liver, O-GlcNAcylation has emerged as an important regulatory mechanism underlying normal liver physiology and metabolic disease. Methods To address whether OGT acts as a critical hepatic nutritional node, mice with a constitutive hepatocyte-specific deletion of OGT (OGTLKO) were generated and challenged with different carbohydrate- and lipid-containing diets. Results Analyses of 4-week-old OGTLKO mice revealed significant oxidative and endoplasmic reticulum stress, and DNA damage, together with inflammation and fibrosis, in the liver. Susceptibility to oxidative and endoplasmic reticulum stress-induced apoptosis was also elevated in OGTLKO hepatocytes. Although OGT expression was partially recovered in the liver of 8-week-old OGTLKO mice, hepatic injury and fibrosis were not rescued but rather worsened with time. Interestingly, weaning of OGTLKO mice on a ketogenic diet (low carbohydrate, high fat) fully prevented the hepatic alterations induced by OGT deletion, indicating that reduced carbohydrate intake protects an OGT-deficient liver. Conclusions These findings pinpoint OGT as a key mediator of hepatocyte homeostasis and survival upon carbohydrate intake and validate OGTLKO mice as a valuable model for assessing therapeutical approaches of advanced liver fibrosis. Impact and Implications Our study shows that hepatocyte-specific deletion of O-GlcNAc transferase (OGT) leads to severe liver injury, reinforcing the importance of O-GlcNAcylation and OGT for hepatocyte homeostasis and survival. Our study also validates the Ogt liver-deficient mouse as a valuable model for the study of advanced liver fibrosis. Importantly, as the severe hepatic fibrosis of Ogt liver-deficient mice could be fully prevented upon feeding on a ketogenic diet (i.e. very-low-carbohydrate, high-fat diet) this work underlines the potential interest of nutritional intervention as antifibrogenic strategies.
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Affiliation(s)
| | - Lucia Parlati
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Fadila Benhamed
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Marion Regnier
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Isadora Cavalcante
- Team Genomics and Signaling of Endocrine Tumors, Institut Cochin, CNRS, INSERM, Université Paris Cité, Paris, France
| | | | | | - Maryline Favier
- HistIM Platform, Institut Cochin, CNRS, INSERM, Université de Paris Cité, Paris, France
| | - Natasa Pavlovic
- Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
| | - Julie Magusto
- Centre de Recherche Saint-Antoine, Sorbonne Université, Inserm, Paris, France
| | - Michèle Cauzac
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Patrick Pagesy
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Jérémie Gautheron
- Centre de Recherche Saint-Antoine, Sorbonne Université, Inserm, Paris, France
| | - Chantal Desdouets
- Team Proliferation, Stress and Liver Physiopathology, Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
| | - Sandra Guilmeau
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Tarik Issad
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
| | - Catherine Postic
- Université Paris Cité, Institut Cochin, CNRS, INSERM, Paris, France
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17
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Tiniakos DG, Anstee QM, Brunt EM, Burt AD. Fatty Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:330-401. [DOI: 10.1016/b978-0-7020-8228-3.00005-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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18
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Chowdhury SG, Karmakar P. Revealing the role of epigenetic and post-translational modulations of autophagy proteins in the regulation of autophagy and cancer: a therapeutic approach. Mol Biol Rep 2023; 51:3. [PMID: 38063905 DOI: 10.1007/s11033-023-08961-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 10/26/2023] [Indexed: 12/18/2023]
Abstract
Autophagy is a process that is characterized by the destruction of redundant components and the removal of dysfunctional ones to maintain cellular homeostasis. Autophagy dysregulation has been linked to various illnesses, such as neurodegenerative disorders and cancer. The precise transcription of the genes involved in autophagy is regulated by a network of epigenetic factors. This includes histone modifications and histone-modifying enzymes. Epigenetics is a broad category of heritable, reversible changes in gene expression that do not include changes to DNA sequences, such as chromatin remodeling, histone modifications, and DNA methylation. In addition to affecting the genes that are involved in autophagy, the epigenetic machinery can also alter the signals that control this process. In cancer, autophagy plays a dual role by preventing the development of tumors on one hand and this process may suppress tumor progression. This may be the control of an oncogene that prevents autophagy while, conversely, tumor suppression may promote it. The development of new therapeutic strategies for autophagy-related disorders could be initiated by gaining a deeper understanding of its intricate regulatory framework. There is evidence showing that certain machineries and regulators of autophagy are affected by post-translational and epigenetic modifications, which can lead to alterations in the levels of autophagy and these changes can then trigger disease or affect the therapeutic efficacy of drugs. The goal of this review is to identify the regulatory pathways associated with post-translational and epigenetic modifications of different proteins in autophagy which may be the therapeutic targets shortly.
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Affiliation(s)
| | - Parimal Karmakar
- Department of Life Science and Biotechnology, Jadavpur University, Kolkata, 700032, India.
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19
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Qian H, Ding WX. SQSTM1/p62 and Hepatic Mallory-Denk Body Formation in Alcohol-Associated Liver Disease. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1415-1426. [PMID: 36906265 PMCID: PMC10642158 DOI: 10.1016/j.ajpath.2023.02.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/14/2023] [Accepted: 02/24/2023] [Indexed: 03/12/2023]
Abstract
Sequestosome 1 (SQSTM1/p62; hereafter p62) is an autophagy receptor protein for selective autophagy primarily due to its direct interaction with the microtubule light chain 3 protein that specifically localizes on autophagosome membranes. As a result, impaired autophagy leads to the accumulation of p62. p62 is also a common component of many human liver disease-related cellular inclusion bodies, such as Mallory-Denk bodies, intracytoplasmic hyaline bodies, α1-antitrypsin aggregates, as well as p62 bodies and condensates. p62 also acts as an intracellular signaling hub, and it involves multiple signaling pathways, including nuclear factor erythroid 2-related factor 2, NF-κB, and the mechanistic target of rapamycin, which are critical for oxidative stress, inflammation, cell survival, metabolism, and liver tumorigenesis. This review discusses the recent insights of p62 in protein quality control, including the role of p62 in the formation and degradation of p62 stress granules and protein aggregates as well as regulation of multiple signaling pathways in the pathogenesis of alcohol-associated liver disease.
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Affiliation(s)
- Hui Qian
- Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas; Department of Internal Medicine, The University of Kansas Medical Center, Kansas City, Kansas.
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20
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Li Y, Kong MW, Jiang N, Ye C, Yao XW, Zou XJ, Hu HM, Liu HT. Vine tea extract ameliorated acute liver injury by inhibiting hepatic autophagy and reversing abnormal bile acid metabolism. Heliyon 2023; 9:e20145. [PMID: 37809393 PMCID: PMC10559920 DOI: 10.1016/j.heliyon.2023.e20145] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Revised: 09/08/2023] [Accepted: 09/13/2023] [Indexed: 10/10/2023] Open
Abstract
Gut microbiota disturbance, autophagy dysregulation, and accumulation of hepatic bile acids (BAs) are essential features of liver injury. Therefore, regulating autophagy and BA metabolism are potential strategies for treating liver diseases. Vine tea has been seen beyond a pleasant tea in food science. Our previous study found that vine tea extract (VTE) intervention alleviated acute liver injury (ALI) by restoring gut microbiota dysbiosis. In this study, we aim to investigate the effect of VTE on carbon tetrachloride (CCl4)-induced hepatic autophagy and BA metabolism disorder in mice. The results showed that VTE effectively suppressed CCl4-induced liver fibrosis and hepatic autophagy. LC-MS/MS assay suggested that VTE affected fecal BA production by reducing the fecal BA levels and improving cholestasis in ALI mice. Besides, VTE inhibited BA synthesis, promoted BA transport in the liver, and enhanced BA reabsorption in the ileum through the farnesoid X receptor (FXR)-related signaling pathway. The hepatic expressions of Fxr and Abca1 were elevated by VTE. Finally, the depletion of gut microbiota in ALI mice had a negative impact on abnormal autophagy and BA metabolism. It was also noted that the administration of VTE did not provide any additional improvement in this regard. Overall, VTE ameliorated ALI by reversing hepatic autophagy and abnormal BA metabolism, and the beneficial effects of VTE on liver injury depended on the existence of gut microbiota.
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Affiliation(s)
- Ying Li
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Ming-Wang Kong
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Nan Jiang
- Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan 430061, PR China
- Hubei Province Academy of Traditional Chinese Medicine, Wuhan 430074, PR China
| | - Chen Ye
- Wuhan Customs Technology Center, Qintai Avenue 588, Wuhan 430050, PR China
| | - Xiao-Wei Yao
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Xiao-Juan Zou
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Hai-Ming Hu
- School of Laboratory Medicine, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
| | - Hong-Tao Liu
- College of Basic Medical Sciences, Hubei University of Chinese Medicine, Huangjiahu West Road 16, Wuhan 430065, PR China
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21
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Akl MG, Li L, Baccetto R, Phanse S, Zhang Q, Trites MJ, McDonald S, Aoki H, Babu M, Widenmaier SB. Complementary gene regulation by NRF1 and NRF2 protects against hepatic cholesterol overload. Cell Rep 2023; 42:112399. [PMID: 37060561 DOI: 10.1016/j.celrep.2023.112399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 10/04/2022] [Accepted: 03/30/2023] [Indexed: 04/16/2023] Open
Abstract
Hepatic cholesterol overload promotes steatohepatitis. Insufficient understanding of liver stress defense impedes therapy development. Here, we elucidate the role of stress defense transcription factors, nuclear factor erythroid 2 related factor-1 (NRF1) and -2 (NRF2), in counteracting cholesterol-linked liver stress. Using a diet that increases liver cholesterol storage, expression profiles and phenotypes of liver from mice with hepatocyte deficiency of NRF1, NRF2, or both are compared with controls, and chromatin immunoprecipitation sequencing is undertaken to identify target genes. Results show NRF1 and NRF2 co-regulate genes that eliminate cholesterol and mitigate inflammation and oxidative damage. Combined deficiency, but not deficiency of either alone, results in severe steatohepatitis, hepatic cholesterol overload and crystallization, altered bile acid metabolism, and decreased biliary cholesterol. Moreover, therapeutic effects of NRF2-activating drug bardoxolone require NRF1 and are supplemented by NRF1 overexpression. Thus, we discover complementary gene programming by NRF1 and NRF2 that counteract cholesterol-associated fatty liver disease progression.
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Affiliation(s)
- May G Akl
- Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada; Department of Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
| | - Lei Li
- Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Raquel Baccetto
- Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Sadhna Phanse
- Department of Chemistry and Biochemistry, University of Regina, Regina, SK, Canada
| | - Qingzhou Zhang
- Department of Chemistry and Biochemistry, University of Regina, Regina, SK, Canada
| | - Michael J Trites
- Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Sherin McDonald
- Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Hiroyuki Aoki
- Department of Chemistry and Biochemistry, University of Regina, Regina, SK, Canada
| | - Mohan Babu
- Department of Chemistry and Biochemistry, University of Regina, Regina, SK, Canada
| | - Scott B Widenmaier
- Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, Saskatoon, SK, Canada.
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22
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Wu Y, Tan HWS, Lin JY, Shen HM, Wang H, Lu G. Molecular mechanisms of autophagy and implications in liver diseases. LIVER RESEARCH 2023; 7:56-70. [PMID: 39959698 PMCID: PMC11792062 DOI: 10.1016/j.livres.2023.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 11/03/2022] [Accepted: 02/15/2023] [Indexed: 02/22/2023]
Abstract
Autophagy is a highly conserved process in which cytosolic contents are degraded by the lysosome, which plays an important role in energy and nutrient balance, and protein or organelle quality control. The liver is the most important organ for metabolism. Studies to date have revealed a significant role of autophagy in the maintenance of liver homeostasis under basal and stressed conditions, and the impairment of autophagy has been closely linked to various liver diseases. Therefore, a comprehensive understanding of the roles of autophagy in liver diseases may help in the development of therapeutic strategies via targeting autophagy. In this review, we will summarize the latest understanding of the molecular mechanisms of autophagy and systematically discuss its implications in various liver diseases, including alcohol-related liver disease, non-alcoholic fatty liver disease, viral hepatitis, hepatocellular carcinoma, and acetaminophen-induced liver injury.
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Affiliation(s)
- Yuankai Wu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hayden Weng Siong Tan
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jin-Yi Lin
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Han-Ming Shen
- Department of Biomedical Sciences, Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, China
| | - Haihe Wang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Guang Lu
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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23
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Liu P, Xu Y, Ye J, Tan J, Hou J, Wang Y, Li J, Cui W, Wang S, Zhao Q. Qingre Huazhuo Jiangsuan Decoction promotes autophagy by inhibiting PI3K/AKT/mTOR signaling pathway to relieve acute gouty arthritis. JOURNAL OF ETHNOPHARMACOLOGY 2023; 302:115875. [PMID: 36328206 DOI: 10.1016/j.jep.2022.115875] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 10/19/2022] [Accepted: 10/22/2022] [Indexed: 06/16/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Gout belongs to the category of "arthralgia syndrome" in traditional Chinese medicine. It is believed that gout is caused by stagnation of blood stasis, heat, and turbid toxin. Qingre Huazhuo Jiangsuan Decoction (QHJD) is a traditional Chinese medicine prescription developed from the classic Chinese medicine prescription Simiao powder to clear heat, remove turbidity, reduce acid, and reduce inflammation. Now Traditional Chinese Medicine (TCM) physicians often apply it to treat acute gouty arthritis (AGA). However, the mechanism of QHJD in relieving acute gouty arthritis is still unclear, and further research is needed. AIM OF THE STUDY Here, we aim to explore the potential mechanism of QHJD in relieving acute gouty arthritis. MATERIALS AND METHODS Acute gouty arthritis model was established by injecting monosodium urate (MSU) suspension into knee joint. The pathological state of synovial tissue in each group was evaluated by hematoxylin-eosin (HE) staining. The level of TNF-α, IL-6, and IL-1β were detected by enzyme-linked immunosorbent assay (ELISA). qRT-PCR was used to detect the mRNA expression of NLRP3, ATG5, ATG7, PI3K, AKT, and mTOR. The protein expression of LC3II/I, p62, ULK1, P-ULK1, Beclin-1, PI3K, AKT, mTOR, P-PI3K, P-AKT, and P-mTOR were detected by Western blot. RESULTS (1) The level of autophagy protein (mRNA) was significantly up-regulated in QHJD group and rapamycin, while the expression of autophagy protein (mRNA) was significantly downregulated in the 3-methyladenoenoic acid (3 MA) group; (2) QHJD and rapamycin significantly inhibited PI3K/AKT/mTOR pathway, while 3 MA group activated this pathway. (3) It was worth noting that after treatment with QHJD and rapamycin, the inflammatory pathological state of AGA synovial tissue was significantly reduced with the activation of the autophagy gene in knee synovial tissue, and the inhibition of PI3K/AKT/mTOR pathway. CONCLUSIONS This research revealed that QHJD activates autophagy by inhibiting PI3K/AKT/mTOR pathway, thereby relieving acute gouty arthritis.
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Affiliation(s)
- Peiyu Liu
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong Province, PR China
| | - Yang Xu
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong Province, PR China
| | - Jiaxue Ye
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong Province, PR China
| | - Jingrui Tan
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong Province, PR China
| | - Jie Hou
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong Province, PR China
| | - Yazhuo Wang
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong Province, PR China
| | - Jianwei Li
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong Province, PR China
| | - Weizhen Cui
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong Province, PR China
| | - Shiyuan Wang
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong Province, PR China.
| | - Qingyang Zhao
- Shandong University of Traditional Chinese Medicine, Jinan, 250355, Shandong Province, PR China.
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24
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Qian H, Chao X, Wang S, Li Y, Jiang X, Sun Z, Rülicke T, Zatloukal K, Ni HM, Ding WX. Loss of SQSTM1/p62 Induces Obesity and Exacerbates Alcohol-Induced Liver Injury in Aged Mice. Cell Mol Gastroenterol Hepatol 2023; 15:1027-1049. [PMID: 36754207 PMCID: PMC10036741 DOI: 10.1016/j.jcmgh.2023.01.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 01/31/2023] [Accepted: 01/31/2023] [Indexed: 02/10/2023]
Abstract
BACKGROUND Alcohol-associated liver disease (ALD) is a worldwide health problem, of which the effective treatment is still lacking. Both detrimental and protective roles of adipose tissue have been implicated in ALD. Although alcohol increases adipose tissue lipolysis to promote alcohol-induced liver injury, alcohol also activates brown adipose tissue (BAT) thermogenesis as an adaptive response in protecting against alcohol-induced liver injury. Moreover, aging and obesity are also risk factors for ALD. In the present study, we investigated the effects of autophagy receptor protein SQSTM1/p62 on adipose tissue and obesity in alcohol-induced liver injury in both young and aged mice. METHODS Young and aged whole-body SQSTM1/p62 knockout (KO) and their age-matched wild-type (WT) mice were subjected to chronic plus binge (Gao-binge) alcohol feeding. Blood, adipose and liver tissues were collected for biochemical and histologic analysis. RESULTS Aged but not young SQSTM1/p62 KO mice had significantly increased body weight and fat mass compared with the matched WT mice. Gao-binge alcohol feeding induced white adipose atrophy and decreased levels of SQSTM1/p62 levels in adipose tissue in aged WT mice. SQSTM1/p62 KO aged mice were resistant to Gao-binge alcohol-induced white adipose atrophy. Alcohol feeding increased the expression of thermogenic genes in WT mouse BAT, which was significantly blunted in SQSTM1/p62 KO aged mice. Alcohol-fed aged SQSTM1/p62 KO mice showed significantly higher levels of serum alanine aminotransferase, hepatic triglyceride, and inflammation compared with young and aged WT mice fed with alcohol. Alcohol-fed SQSTM1/p62 KO mice also increased secretion of proinflammatory and angiogenic adipokines that may promote alcohol-induced liver injury. CONCLUSIONS Loss of SQSTM1/p62 in aged mice leads to obesity and impairs alcohol-induced BAT adaptation, resulting in exacerbated alcohol-induced liver injury in mice.
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Affiliation(s)
- Hui Qian
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Shaogui Wang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Yuan Li
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Xiaoxiao Jiang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Zhaoli Sun
- Department of Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Thomas Rülicke
- Department of Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria
| | - Kurt Zatloukal
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas; Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
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25
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Liu Y, Trnka MJ, He L, Burlingame AL, Correia MA. In-Cell Chemical Crosslinking Identifies Hotspots for SQSTM-1/p62-IκBα Interaction That Underscore a Critical Role of p62 in Limiting NF-κB Activation Through IκBα Stabilization. Mol Cell Proteomics 2023; 22:100495. [PMID: 36634736 PMCID: PMC9947424 DOI: 10.1016/j.mcpro.2023.100495] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 01/02/2023] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
We have previously documented that in liver cells, the multifunctional protein scaffold p62/SQSTM1 is closely associated with IκBα, an inhibitor of the transcriptional activator NF-κB. Such an intimate p62-IκBα association we now document leads to a marked 18-fold proteolytic IκBα-stabilization, enabling its nuclear entry and termination of the NF-κB-activation cycle. In p62-/--cells, such termination is abrogated resulting in the nuclear persistence and prolonged activation of NF-κB following inflammatory stimuli. Utilizing various approaches both classic (structural deletion, site-directed mutagenesis) as well as novel (in-cell chemical crosslinking), coupled with proteomic analyses, we have defined the precise structural hotspots of p62-IκBα association. Accordingly, we have identified such IκBα hotspots to reside around N-terminal (K38, K47, and K67) and C-terminal (K238/C239) residues in its fifth ankyrin repeat domain. These sites interact with two hotspots in p62: One in its PB-1 subdomain around K13, and the other comprised of a positively charged patch (R183/R186/K187/K189) between its ZZ- and TB-subdomains. APEX proximity analyses upon IκBα-cotransfection of cells with and without p62 have enabled the characterization of the p62 influence on IκBα-protein-protein interactions. Interestingly, consistent with p62's capacity to proteolytically stabilize IκBα, its presence greatly impaired IκBα's interactions with various 20S/26S proteasomal subunits. Furthermore, consistent with p62 interaction with IκBα on an interface opposite to that of its NF-κB-interacting interface, p62 failed to significantly affect IκBα-NF-κB interactions. These collective findings together with the known dynamic p62 nucleocytoplasmic shuttling leads us to speculate that it may be involved in "piggy-back" nuclear transport of IκBα following its NF-κB-elicited transcriptional activation and de novo synthesis, required for termination of the NF-κB-activation cycle. Consequently, mice carrying a liver-specific deletion of p62-residues 68 to 252 reveal age-dependent-enhanced liver inflammation. Our findings reveal yet another mode of p62-mediated pathophysiologically relevant regulation of NF-κB.
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Affiliation(s)
- Yi Liu
- Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA
| | - Michael J Trnka
- Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA
| | - Liang He
- Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA
| | - A L Burlingame
- Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA
| | - Maria Almira Correia
- Department of Cellular & Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, California, USA; Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA; The Liver Center, University of California San Francisco, San Francisco, California, USA.
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Huang Y, Yan S, Dong X, Jiao X, Wang S, Li D, Wang G. Deficiency of MST1 in endometriosis related peritoneal macrophages promoted the autophagy of ectopic endometrial stromal cells by IL-10. Front Immunol 2022; 13:993788. [PMID: 36263059 PMCID: PMC9575673 DOI: 10.3389/fimmu.2022.993788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/06/2022] [Indexed: 11/15/2022] Open
Abstract
Changes in the function of peritoneal macrophages contribute to the homeostasis of the peritoneal immune microenvironment in endometriosis. The mechanism by which ectopic tissues escape phagocytic clearance by macrophages to achieve ectopic colonization and proliferation is unknown. The expression of CD163 in peritoneal macrophages in patients with endometriosis is increased, with the overexpression of MAPK, which can promote the M2-type polarization of macrophages and reduce their ability to phagocytose ectopic endometrial cells. As an upstream regulator of MAPK, MST1 expression is deficient in peritoneal macrophages of patients with endometriosis. This process is regulated by miR-887-5p, a noncoding RNA targeting MST1. Moreover, MST1-knockout macrophages secrete anti-inflammatory factor IL-10, which promotes autophagy of ectopic endometrial stromal cells. These results suggest that MST1 deficient macrophages may accelerate the autophagy of ectopic endometrium via IL-10 which was regulated by miR-887-5p.
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Affiliation(s)
- Yufei Huang
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Gynecology Laboratory, Shandong Provincial Hospital, Jinan, Shandong, China
| | - Shumin Yan
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Gynecology Laboratory, Shandong Provincial Hospital, Jinan, Shandong, China
| | - Xiaoyu Dong
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Gynecology Laboratory, Shandong Provincial Hospital, Jinan, Shandong, China
| | - Xue Jiao
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Gynecology Laboratory, Shandong Provincial Hospital, Jinan, Shandong, China
| | - Shuang Wang
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Gynecology Laboratory, Shandong Provincial Hospital, Jinan, Shandong, China
| | - Dong Li
- Cryomedicine Laboratory, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Guoyun Wang
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Medical Integration and Practice Center, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
- Gynecology Laboratory, Shandong Provincial Hospital, Jinan, Shandong, China
- *Correspondence: Guoyun Wang,
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Liu Z, Huang Y, Jin X, Liu L, Gu H. PCB153 suppressed autophagy via PI3K/Akt/mTOR and RICTOR/Akt/mTOR signaling by the upregulation of microRNA-155 in rat primary chondrocytes. Toxicol Appl Pharmacol 2022; 449:116135. [PMID: 35732230 DOI: 10.1016/j.taap.2022.116135] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 06/07/2022] [Accepted: 06/15/2022] [Indexed: 02/04/2023]
Abstract
Polychlorinated biphenyls (PCBs) are a typical type of persistent organic pollutant. PCB exposure is associated to the occurrence and development of osteoarthritis (OA); however, the involved mechanisms have yet to be elucidated. Here, we investigated the pro-osteoarthritic effect of 2, 2', 4, 4', 5, 5'-hexachlorobiphenyl (PCB153), and the involvement of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) and the RICTOR/Akt/mTOR signaling pathways. PCB153 of 20 and 30 μM increased the expression of MMP13 and decreased the expression of type II collagen, in a concentration-dependent manner. PCB153 treatment reduced the expression of Beclin 1 and LC3B, but increased the expression of p62 by upregulating miR-155 levels. PCB153 treatment activated the PI3K/Akt/mTOR signaling pathway by upregulating miR-155 levels. RICTOR was involved in activating the Akt/mTOR signaling pathway, and was also regulated by miR-155. In conclusion, PCB153 could promote the degradation of the extracellular matrix of chondrocytes by upregulating miR-155 via a mechanism related to the activation of the PI3K/Akt/mTOR and RICTOR/Akt/mTOR signaling pathway, which suppressed autophagy and facilitated the development of OA. MiR-155 may represent potential therapeutic targets to alleviate the development of OA.
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Affiliation(s)
- Ziyu Liu
- Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, 110122, China
| | - Yue Huang
- Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, 110122, China
| | - Xin Jin
- Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, 110122, China
| | - Li Liu
- Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, 110122, China
| | - Hailun Gu
- Department of Orthopedics, Shengjing Hospital, China Medical University, 110004, China.
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Xue F, Cheng J, Liu Y, Cheng C, Zhang M, Sui W, Chen W, Hao P, Zhang Y, Zhang C. Cardiomyocyte-specific knockout of ADAM17 ameliorates left ventricular remodeling and function in diabetic cardiomyopathy of mice. Signal Transduct Target Ther 2022; 7:259. [PMID: 35909160 PMCID: PMC9339545 DOI: 10.1038/s41392-022-01054-3] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 05/06/2022] [Accepted: 06/05/2022] [Indexed: 02/08/2023] Open
Abstract
Angiotensin-converting enzyme 2 (ACE2) has proven beneficial in attenuating diabetic cardiomyopathy (DCM) but has been found to be a substrate of a disintegrin and metalloprotease protein-17 (ADAM17). However, whether ADAM17 plays a role in the pathogenesis and intervention of DCM is obscure. In this study, we created cardiomyocyte-specific knockout of ADAM17 (A17α-MHCKO) mice, and left ventricular dimension, function, pathology and molecular biology were assessed in ADAM17fl/fl control, A17α-MHCKO control, ADAM17fl/fl diabetic and A17α-MHCKO diabetic mice. Both differentiated H9c2 cells and neonatal rat cardiomyocytes (NRCMs) were used to explore the molecular mechanisms underlying the effect of ADAM17 on DCM. The results showed that protein expression and activity of ADAM17 were upregulated whereas the protein expression of ACE2 was downregulated in the myocardium of diabetic mice. Cardiomyocyte-specific knockout of ADAM17 mitigated cardiac fibrosis and cardiomyocyte apoptosis and ameliorated cardiac dysfunction in mice with DCM. Bioinformatic analyses detected a number of genes enriched in metabolic pathways, in particular the AMPK signaling pathway, expressed differentially between the hearts of A17α-MHCKO and ADAM17fl/fl diabetic mice. The mechanism may involve activated AMPK pathway, increased autophagosome formation and improved autophagic flux, which reduced the apoptotic response in cardiomyocytes. In addition, hypoxia-inducible factor-1α (HIF-1α) might act as an upstream mediator of upregulated ADAM17 and ADAM17 might affect AMPK signaling via α1 A-adrenergic receptor (ADRA1A). These results indicated that ADAM17 activity and ACE2 shedding were enhanced in DCM, which was reversed by cardiomyocyte-specific ADAM17 knockout. Thus, inhibition of ADAM17 may provide a promising approach to the treatment of DCM.
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Affiliation(s)
- Fei Xue
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Jing Cheng
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China
| | - Yanping Liu
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Cheng Cheng
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Meng Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Wenhai Sui
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Wenqiang Chen
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Panpan Hao
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
| | - Yun Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
- Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China.
| | - Cheng Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
- Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China.
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Cook JJ, Wei M, Segovia B, Cosio-Lima L, Simpson J, Taylor S, Koh Y, Kim S, Lee Y. Endurance exercise-mediated metabolic reshuffle attenuates high-caloric diet-induced non-alcoholic fatty liver disease. Ann Hepatol 2022; 27:100709. [PMID: 35489641 DOI: 10.1016/j.aohep.2022.100709] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/17/2022] [Accepted: 04/04/2022] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND AIM Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases in the United States. Metabolic distress (obese diabetes) is the main causative element of NAFLD. While there is no cure for NAFLD, endurance exercise (EEx) has emerged as a therapeutic strategy against NAFLD. However, mechanisms of EXE-induced hepatic protection especially in female subjects remain unidentified. Thus, the aim of the study is to examine molecular mechanisms of EXE-induced hepatic protection against diet-induced NAFLD in female mice. MATERIAL AND METHODS Nine-week-old female C57BL/6J mice were randomly divided into three groups: normal-diet control group (CON, n=11); high-fat diet/high-fructose group (HFD/HF, n=11); and HFD/HF+EEx group (HFD/HF+EEx, n=11). The mice assigned to HFD/HF and HFD/HF+EEx groups were fed with HFD/HF for 12 weeks, after which the mice assigned to the EEx group began treadmill exercise for 12 weeks, with HFD/HF continued. RESULTS EEx attenuated hepatic steatosis, reduced de novo lipogenesis (reduction in ATP-Citrate- Lyase and diacylglycerol-O-acyltransferase 1), and enhanced mitochondrial biogenesis and fatty-acid activation (oxidative phosphorylation enzymes and Acyl-CoA synthetase1). Also, EEx prevented upregulation of gluconeogenic proteins (glyceraldehyde-3-phosphate dehydrogenase, glucose-6-phosphatase, and phosphoenolpyruvate-carboxykinase1), premature senescence (suppression of p53, p22, and p16, tumor-necrosis-factor-α, and interleukin-1β, and oxidative stress), and autophagy deficiency. Furthermore, EXE reversed apoptosis arrest (cleaved cysteine-dependent-aspartate-directed protease3 and Poly-(ADP-ribose)-polymerase1). CONCLUSION EEx-mediated reparations of metabolic and redox imbalance (utilization of pentose phosphate pathway), and autophagy deficiency caused by metabolic distress critically contribute to preventing/delaying severe progression of NAFLD. Also, EEx-induced anti-senescence and cell turnover are crucial protective mechanisms against NAFLD.
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Affiliation(s)
- Joshua J Cook
- Molecular and Cellular Exercise Physiology Laboratory, Department of Movement Sciences and Health, Usha Kundu, MD College of Health, University of West Florida, Pensacola, FL 32514, USA
| | - Madeline Wei
- Molecular and Cellular Exercise Physiology Laboratory, Department of Movement Sciences and Health, Usha Kundu, MD College of Health, University of West Florida, Pensacola, FL 32514, USA
| | - Benny Segovia
- Molecular and Cellular Exercise Physiology Laboratory, Department of Movement Sciences and Health, Usha Kundu, MD College of Health, University of West Florida, Pensacola, FL 32514, USA
| | - Ludmila Cosio-Lima
- Molecular and Cellular Exercise Physiology Laboratory, Department of Movement Sciences and Health, Usha Kundu, MD College of Health, University of West Florida, Pensacola, FL 32514, USA
| | - Jeffrey Simpson
- Molecular and Cellular Exercise Physiology Laboratory, Department of Movement Sciences and Health, Usha Kundu, MD College of Health, University of West Florida, Pensacola, FL 32514, USA
| | - Scott Taylor
- Department of Biology, Hal Marcus College of Science and Engineering, University of West Florida, Pensacola, FL 32514, USA
| | - Yunsuk Koh
- Department of Health, Human Performance and Recreation, Robbins College of Human Sciences, Baylor University, Waco, TX 76798, USA
| | - Sangho Kim
- Department of Sport Science, College of Culture and Sports, School of Global Sport Studies, Korea University, Sejong 30019, South Korea
| | - Youngil Lee
- Molecular and Cellular Exercise Physiology Laboratory, Department of Movement Sciences and Health, Usha Kundu, MD College of Health, University of West Florida, Pensacola, FL 32514, USA.
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Yin B, Wang YB, Li X, Hou XW. β‑aminoisobutyric acid ameliorates hypertensive vascular remodeling via activating the AMPK/SIRT1 pathway in VSMCs. Bioengineered 2022; 13:14382-14401. [PMID: 36694438 PMCID: PMC9995136 DOI: 10.1080/21655979.2022.2085583] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) play a fundamental role in the pathogenesis of hypertension-related vascular remodeling. β-aminoisobutyric acid (BAIBA) is a nonprotein β-amino acid with multiple pharmacological actions. Recently, BAIBA has been shown to attenuate salt‑sensitive hypertension, but the role of BAIBA in hypertension-related vascular remodeling has yet to be fully clarified. This study examined the potential roles and underlying mechanisms of BAIBA in VSMC proliferation and migration induced by hypertension. Primary VSMCs were cultured from the aortas of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Our results showed that BAIBA pretreatment obviously alleviated the phenotypic transformation, proliferation, and migration of SHR-derived VSMCs. Exogenous BAIBA significantly inhibited the release of inflammatory cytokines by diminishing phosphorylation and nuclear translocation of p65 NFκB, retarding IκBα phosphorylation and degradation, as well as erasing STAT3 phosphorylation in VSMCs. Supplementation of BAIBA triggered Nrf2 dissociation from Keap1 and inhibited oxidative stress in VSMCs from SHR. Mechanistically, activation of the AMPK/sirtuin 1 (SIRT1) axis was required for BAIBA to cube hypertension-induced VSMC proliferation, migration, oxidative damage and inflammatory response. Most importantly, exogenous BAIBA alleviated hypertension, ameliorated vascular remodeling and fibrosis, abated vascular oxidative burst and inflammation in SHR, an effect that was abolished by deficiency of AMPKα1 and SIRT1. BAIBA might serve as a novel therapeutic agent to prevent vascular remodeling in the context of hypertension.
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Affiliation(s)
- Bo Yin
- Department of General Surgery, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Yu-Bin Wang
- Department of General Surgery, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Xiang Li
- Department of General Surgery, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Xu-Wei Hou
- Department of Human Anatomy, Jinzhou Medical University, Jinzhou, Liaoning, China
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Xu LL, Chen YK, Zhang QY, Chen LJ, Zhang KK, Li JH, Liu JL, Wang Q, Xie XL. Gestational exposure to GenX induces hepatic alterations by the gut-liver axis in maternal mice: A similar mechanism as PFOA. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 820:153281. [PMID: 35066053 DOI: 10.1016/j.scitotenv.2022.153281] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 01/09/2022] [Accepted: 01/16/2022] [Indexed: 05/27/2023]
Abstract
GenX is an alternative to perfluorooctanoic acid (PFOA) and was included in the accession list of Substances of Very High Concern in 2019. Gestational GenX exposure induces maternal hepatotoxicity in animals. However, the mechanisms of GenX toxicity have not been explored. In the present study, pregnant Balb/c mice were administered with PFOA (1 mg/kg BW/day), GenX (2 mg/kg BW/day), or Milli-Q water by gavage during gestation. Similar hepatic pathological changes, including enlargement of hepatocytes, cytoplasm loss, nucleus migration, inflammatory cell infiltration, and reduction of glycogen storage, were observed in PFOA and GenX groups. Increased expression levels of indicators of the TLR4 pathway indicated activation of inflammation in the liver of maternal mice after exposure to PFOA or GenX, consistent with the pathological changes. Overexpression of cleaved PARP-1, cleaved caspase 3, Bax and decreased Bcl-2 proteins indicated activation of apoptosis, whereas overexpression of ULK-1, p62, beclin-1, LC3-II proteins and downregulation of p-mTOR implied that PFOA and GenX exposure initiated autophagy. Decreased secretion of mucus, reduced expression levels of tight junction proteins, and higher serum levels of lipopolysaccharide indicated disruption of the intestinal barrier. Translocation of lipopolysaccharide may be recognized by TLR4, thus triggering inflammatory pathway in the maternal liver. In summary, gestational exposure to PFOA or GenX induced maternal hepatic alterations through the gut-liver axis.
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Affiliation(s)
- Ling-Ling Xu
- Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), No. 1838 North Guangzhou Road, 510515 Guangzhou, China
| | - Yu-Kui Chen
- Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), No. 1838 North Guangzhou Road, 510515 Guangzhou, China
| | - Qin-Yao Zhang
- Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), No. 1838 North Guangzhou Road, 510515 Guangzhou, China
| | - Li-Jian Chen
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1838 North Guangzhou Road, 510515 Guangzhou, China
| | - Kai-Kai Zhang
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1838 North Guangzhou Road, 510515 Guangzhou, China
| | - Jia-Hao Li
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1838 North Guangzhou Road, 510515 Guangzhou, China
| | - Jia-Li Liu
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1838 North Guangzhou Road, 510515 Guangzhou, China
| | - Qi Wang
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1838 North Guangzhou Road, 510515 Guangzhou, China.
| | - Xiao-Li Xie
- Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), No. 1838 North Guangzhou Road, 510515 Guangzhou, China.
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Qian H, Bai Q, Yang X, Akakpo JY, Ji L, Yang L, Rülicke T, Zatloukal K, Jaeschke H, Ni HM, Ding WX. Dual roles of p62/SQSTM1 in the injury and recovery phases of acetaminophen-induced liver injury in mice. Acta Pharm Sin B 2021; 11:3791-3805. [PMID: 35024307 PMCID: PMC8727897 DOI: 10.1016/j.apsb.2021.11.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 11/05/2021] [Accepted: 11/08/2021] [Indexed: 12/15/2022] Open
Abstract
Acetaminophen (APAP) overdose can induce liver injury and is the most frequent cause of acute liver failure in the United States. We investigated the role of p62/SQSTM1 (referred to as p62) in APAP-induced liver injury (AILI) in mice. We found that the hepatic protein levels of p62 dramatically increased at 24 h after APAP treatment, which was inversely correlated with the hepatic levels of APAP-adducts. APAP also activated mTOR at 24 h, which is associated with increased cell proliferation. In contrast, p62 knockout (KO) mice showed increased hepatic levels of APAP-adducts detected by a specific antibody using Western blot analysis but decreased mTOR activation and cell proliferation with aggravated liver injury at 24 h after APAP treatment. Surprisingly, p62 KO mice recovered from AILI whereas the wild-type mice still sustained liver injury at 48 h. We found increased number of infiltrated macrophages in p62 KO mice that were accompanied with decreased hepatic von Willebrand factor (VWF) and platelet aggregation, which are associated with increased cell proliferation and improved liver injury at 48 h after APAP treatment. Our data indicate that p62 inhibits the late injury phase of AILI by increasing autophagic selective removal of APAP-adducts and mitochondria but impairs the recovery phase of AILI likely by enhancing hepatic blood coagulation.
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Key Words
- 4EBP-1, translational initiation factor 4E binding protein-1
- AILI, APAP-induced liver injury
- ALT, alanine aminotransferase
- APAP, acetaminophen
- APAP-AD, APAP-adducts
- Autophagy
- CLEC-2, C-type lectin-like receptor
- CYP2E1, cytochrome P450 2E
- Coagulation
- DILI
- GCL, glutamate cysteine ligase
- GSH, glutathione
- H&E, hematoxylin and eosin
- Hepatotoxicity
- KC, Kupffer cells
- KEAP1, Kelch-like ECH-associated protein-1
- KIR, KEAP1-interacting region
- KO, knockout
- LC3, microtubule-associated light chain 3
- Liver regeneration
- Macrophage
- NAC, N-acetylcysteine
- NAPQI, N-acetyl-p-benzoquinone imine
- NF-κB, nuclear factor-κB
- NPCs, non-parenchymal cells
- NQO1, NADPH quinone dehydrogenase 1
- NRF2, nuclear factor erythroid 2-related factor 2
- Platelet
- S6, ribosomal protein S6 kinase
- TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling
- VWF, von Willebrand factor
- WT, wild type
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Affiliation(s)
- Hui Qian
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Qingyun Bai
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- School of Chemistry and Bioengineering, Yichun University, Yichun 336000, China
| | - Xiao Yang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jephte Y. Akakpo
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Lili Ji
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Li Yang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Thomas Rülicke
- Department of Biomedical Sciences, University of Veterinary Medicine Vienna Veterinärplatz, Vienna 1210, Austria
| | - Kurt Zatloukal
- The Institute of Pathology, Medical University of Graz, Graz A-8036, Austria
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Hong-Min Ni
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA
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Priming, Triggering, Adaptation and Senescence (PTAS): A Hypothesis for a Common Damage Mechanism of Steatohepatitis. Int J Mol Sci 2021; 22:ijms222212545. [PMID: 34830427 PMCID: PMC8624051 DOI: 10.3390/ijms222212545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/18/2021] [Accepted: 11/19/2021] [Indexed: 11/17/2022] Open
Abstract
Understanding the pathomechanism of steatohepatitis (SH) is hampered by the difficulty of distinguishing between causes and consequences, by the broad spectrum of aetiologies that can produce the phenotype, and by the long time-span during which SH develops, often without clinical symptoms. We propose that SH develops in four phases with transitions: (i) priming lowers stress defence; (ii) triggering leads to acute damage; (iii) adaptation, possibly associated with cellular senescence, mitigates tissue damage, leads to the phenotype, and preserves liver function at a lower level; (iv) finally, senescence prevents neoplastic transformation but favours fibrosis (cirrhosis) and inflammation and further reduction in liver function. Escape from senescence eventually leads to hepatocellular carcinoma. This hypothesis for a pathomechanism of SH is supported by clinical and experimental observations. It allows organizing the various findings to uncover remaining gaps in our knowledge and, finally, to provide possible diagnostic and intervention strategies for each stage of SH development.
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Peng QB, Zhu SY, Wang WY. Autophagy mediated by the HGF/Met/JNK signaling pathway is involved in carcinogenesis of liver cirrhosis. Shijie Huaren Xiaohua Zazhi 2021; 29:1158-1166. [DOI: 10.11569/wcjd.v29.i20.1158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver cancer stem cell-like cells (CSCs) have strong self-renewal and tumorigenic capabilities, and play a key role in the progression of liver cirrhosis to liver cancer. We identified liver Axin2+CD90+ cells as CSCs in liver cirrhosis, and observed the effect of autophagy mediated by the HGF/Met/JN signaling pathway during the progression of liver cirrhosis to liver cancer.
AIM To determine the role of HGF/Met/JNK signaling pathway-mediated autophagy in the carcinogenesis of liver cirrhosis and the effect of c-Met inhibitor on this process.
METHODS Eight non-cirrhotic surgical specimens were collected from patients with hepatic hemangioma. In September 2007, 18 alcohol-related and 30 chronic hepatitis B-related cirrhosis biopsy samples were collected in our hospital. These patients were followed until December 2015. Three surgical liver cancer samples from patients with alcohol-related cirrhosis, and eight liver cancer samples from patients with hepatitis B-related cirrhosis were collected by surgery. Eight-week-old male SD rats were injected intraperitoneally with 50 mg/kg diethylnitrosamine twice a week for 8 wk to establish a liver cirrhosis model. Western blot was used to detect tissue autophagy status, HGF levels, and changes in HGF/Met/JNK signaling pathway molecules in humans and rats. The c-Met inhibitor EMD1214063 was used to treat cirrhotic rats, evaluate cell proliferation and apoptosis, and assess changes in HGF/Met/JNK signaling pathway molecules.
RESULTS Compared with normal liver tissue, the level of autophagy in cirrhosis was significantly increased (P < 0.05), while the decrease in autophagy was associated with the progression of cirrhosis to liver cancer. At the same time, the production of HGF in these abnormal samples was significantly increased. The liver cirrhosis tissue was first stratified according to autophagy status and HGF expression, and the levels of p-Met, t-Met, and p-JNK were found to be significantly elevated in autophagy-enhanced Axin2-positive cells (P < 0.05). Cell proliferation was significantly reduced after 8 and 11 wk of treatment (P < 0.05), and TUNEL staining showed that the c-Met inhibitor EMD1214063 had no significant effect on hepatocyte apoptosis. Western blot analysis using whole liver lysates from control and EMD1214063 treated groups at weeks 8 and 11 showed that the levels of p-Met, p-JNK, and HGF were significantly reduced at both time points.
CONCLUSION HGF/Met/JNK signaling pathway-mediated autophagy is involved in the carcinogenesis of cirrhosis, and c-Met inhibitors can play a therapeutic role in this process.
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Affiliation(s)
- Quan-Bin Peng
- Department of Gastroenterology, Second People's Hospital of Lishui, Lishui 323000, Zhejiang Province, China
| | - Shu-Yuan Zhu
- Department of Gastroenterology, Second People's Hospital of Lishui, Lishui 323000, Zhejiang Province, China
| | - Wang-Yue Wang
- Department of Gastroenterology, Zhejiang Provincial People's Hospital, Hangzhou 310014, Zhejiang Province, China
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Qian H, Chao X, Williams J, Fulte S, Li T, Yang L, Ding WX. Autophagy in liver diseases: A review. Mol Aspects Med 2021; 82:100973. [PMID: 34120768 DOI: 10.1016/j.mam.2021.100973] [Citation(s) in RCA: 215] [Impact Index Per Article: 53.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 05/29/2021] [Accepted: 05/30/2021] [Indexed: 02/07/2023]
Abstract
The liver is a highly dynamic metabolic organ that plays critical roles in plasma protein synthesis, gluconeogenesis and glycogen storage, cholesterol metabolism and bile acid synthesis as well as drug/xenobiotic metabolism and detoxification. Research from the past decades indicate that autophagy, the cellular catabolic process mediated by lysosomes, plays an important role in maintaining cellular and metabolic homeostasis in the liver. Hepatic autophagy fluctuates with hormonal cues and the availability of nutrients that respond to fed and fasting states as well as circadian activities. Dysfunction of autophagy in liver parenchymal and non-parenchymal cells can lead to various liver diseases including non-alcoholic fatty liver diseases, alcohol associated liver disease, drug-induced liver injury, cholestasis, viral hepatitis and hepatocellular carcinoma. Therefore, targeting autophagy may be a potential strategy for treating these various liver diseases. In this review, we will discuss the current progress on the understanding of autophagy in liver physiology. We will also discuss several forms of selective autophagy in the liver and the molecular signaling pathways in regulating autophagy of different cell types and their implications in various liver diseases.
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Affiliation(s)
- Hui Qian
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Jessica Williams
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Sam Fulte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA
| | - Tiangang Li
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 73104, USA
| | - Ling Yang
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS, 66160, USA.
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Chua JP, De Calbiac H, Kabashi E, Barmada SJ. Autophagy and ALS: mechanistic insights and therapeutic implications. Autophagy 2021; 18:254-282. [PMID: 34057020 PMCID: PMC8942428 DOI: 10.1080/15548627.2021.1926656] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Mechanisms of protein homeostasis are crucial for overseeing the clearance of misfolded and toxic proteins over the lifetime of an organism, thereby ensuring the health of neurons and other cells of the central nervous system. The highly conserved pathway of autophagy is particularly necessary for preventing and counteracting pathogenic insults that may lead to neurodegeneration. In line with this, mutations in genes that encode essential autophagy factors result in impaired autophagy and lead to neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS). However, the mechanistic details underlying the neuroprotective role of autophagy, neuronal resistance to autophagy induction, and the neuron-specific effects of autophagy-impairing mutations remain incompletely defined. Further, the manner and extent to which non-cell autonomous effects of autophagy dysfunction contribute to ALS pathogenesis are not fully understood. Here, we review the current understanding of the interplay between autophagy and ALS pathogenesis by providing an overview of critical steps in the autophagy pathway, with special focus on pivotal factors impaired by ALS-causing mutations, their physiologic effects on autophagy in disease models, and the cell type-specific mechanisms regulating autophagy in non-neuronal cells which, when impaired, can contribute to neurodegeneration. This review thereby provides a framework not only to guide further investigations of neuronal autophagy but also to refine therapeutic strategies for ALS and related neurodegenerative diseases.Abbreviations: ALS: amyotrophic lateral sclerosis; Atg: autophagy-related; CHMP2B: charged multivesicular body protein 2B; DPR: dipeptide repeat; FTD: frontotemporal dementia; iPSC: induced pluripotent stem cell; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; PINK1: PTEN induced kinase 1; RNP: ribonuclear protein; sALS: sporadic ALS; SPHK1: sphingosine kinase 1; TARDBP/TDP-43: TAR DNA binding protein; TBK1: TANK-binding kinase 1; TFEB: transcription factor EB; ULK: unc-51 like autophagy activating kinase; UPR: unfolded protein response; UPS: ubiquitin-proteasome system; VCP: valosin containing protein.
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Affiliation(s)
- Jason P Chua
- Department of Neurology, University of Michigan, Ann Arbor, MI, United States
| | - Hortense De Calbiac
- Recherche translationnelle sur les maladies neurologiques, Institut Imagine, UMR-1163 INSERM et Université Paris Descartes, Hôpital Universitaire Necker-Enfants Malades, Paris, France
| | - Edor Kabashi
- Recherche translationnelle sur les maladies neurologiques, Institut Imagine, UMR-1163 INSERM et Université Paris Descartes, Hôpital Universitaire Necker-Enfants Malades, Paris, France
| | - Sami J Barmada
- Department of Neurology, University of Michigan, Ann Arbor, MI, United States
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Transcriptome Analysis and Autophagy Investigation of LoVo Cells Stimulated with Exosomes Derived from T. asiatica Adult Worms. Microorganisms 2021; 9:microorganisms9050994. [PMID: 34062985 PMCID: PMC8147967 DOI: 10.3390/microorganisms9050994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 04/25/2021] [Accepted: 04/28/2021] [Indexed: 11/17/2022] Open
Abstract
Taenia asiatica is a zoonotic parasite found in the human intestine and pig liver that evolved various strategies to survive the host’s defenses. Exosomes are membranous vesicles released by cells and are an important vehicle in parasite-host interactions. However, no literature exists on the specific infection mechanisms of T. asiatica against the host defense response, and further research is required to understand the parasite-host interaction. In this study, we investigated the host’s differentially expressed genes (DEGs) while stimulating them with exosomes derived from the T. asiatica adult worm (Tas-exo) on LoVo by RNA-seq analysis. Our results identified 348 genes as being significantly differentially expressed for the Tas-exo group when comparing with that of the NC group. Some of these genes are related to modulation of cell proliferation and cell autophagy. Surprisingly, autophagy and cell proliferation have crucial roles in the defense against parasites; accordingly, we detected cell proliferation and autophagy in LoVo cells by CCK8, immunofluorescence, and Western blotting, demonstrating that Tas-exo could inhibit LoVo cell proliferation and autophagy via AMPK pathway. When P62 and p-mTOR/mTOR expression were significantly increased, BeclinI and pAMPK/AMPK were significantly decreased. These results expand our understanding of parasite-host interactions mediated by exosomes.
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Roychowdhury S, Gandhirajan A, Kibler C, Wang X, Vachharajani V. Sirtuin 2 Dysregulates Autophagy in High-Fat-Exposed Immune-Tolerant Macrophages. Cells 2021; 10:731. [PMID: 33810233 PMCID: PMC8066127 DOI: 10.3390/cells10040731] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/22/2021] [Accepted: 03/23/2021] [Indexed: 12/29/2022] Open
Abstract
Obesity increases morbidity and resource utilization in sepsis patients. The immune response in sepsis transitions from an endotoxin-responsive hyper- to an endotoxin-tolerant hypo-inflammatory phase. The majority of sepsis mortality occurs during hypo-inflammation. We reported prolonged hypo-inflammation with increased sirtuin 2 (SIRT2) expression in obese-septic mice. The effect of direct exposure to high-fat/free fatty acid (FFA) and the role of SIRT2 in immune cells during the transition to hypo-inflammation is not well-understood. Autophagy, a degradation process of damaged protein/organelles, is dysregulated during sepsis. Here, we investigated the effect of direct FFA exposure and the role of SIRT2 expression on autophagy as macrophages transition from hyper-to hypo-inflammation. We found, FFA-exposed RAW 264.7 cells with lipopolysaccharide (LPS) stimulation undergo endotoxin-sensitive ("sensitive") hyper- followed by endotoxin tolerant ("tolerant") hypo-inflammatory phases; SIRT2 expression increases significantly in tolerant cells. Autophagy proteins LC3b-II, and beclin-1 increase in FFA-sensitive and decrease in tolerant cells; p62 expressions continue to accumulate in tolerant cells. We observed that SIRT2 directly deacetylates α-tubulin and impairs autophagy clearance. Importantly, we find SIRT2 inhibitor AK-7 treatment during endotoxin tolerant phase reverses autophagy dysregulation with improved autophagy clearance in FFA-tolerant cells. Thus, we report impaired autophagosome formation and autophagy clearance via increased SIRT2 expression in FFA-exposed tolerant macrophages.
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Affiliation(s)
- Sanjoy Roychowdhury
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, OH 44195, USA; (S.R.); (A.G.); (C.K.)
| | - Anugraha Gandhirajan
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, OH 44195, USA; (S.R.); (A.G.); (C.K.)
| | - Christopher Kibler
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, OH 44195, USA; (S.R.); (A.G.); (C.K.)
| | - Xianfeng Wang
- Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA;
| | - Vidula Vachharajani
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland, OH 44195, USA; (S.R.); (A.G.); (C.K.)
- Department of Critical Care, Respiratory Institute, Cleveland Clinic, Cleveland, OH 44195, USA
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Ho CY, Chang AC, Hsu CH, Tsai TF, Lin YC, Chou KY, Chen HE, Lin JF, Chen PC, Hwang TIS. Miconazole induces protective autophagy in bladder cancer cells. ENVIRONMENTAL TOXICOLOGY 2021; 36:185-193. [PMID: 32981224 DOI: 10.1002/tox.23024] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 07/17/2020] [Accepted: 08/28/2020] [Indexed: 06/11/2023]
Abstract
Autophagy plays a dual function in cancer progression; autophagy activation can support cancer cell survival or contribute to cell death. Miconazole, a Food and Drug Administration-approved antifungal drug, has been implicated in oncology research recently. Miconazole was found to exert antitumor effects in various tumors, including bladder cancer (BC). However, whether it provokes protective autophagy has been never discussed. We provide evidence that miconazole induces protective autophagy in BC for the first time. The results indicated that 1A/1B-light chain 3 (LC3)-II processing and p62 expression were elevated after miconazole exposure. Also, adenosine monophosphate-activated protein kinase phosphorylation was increased after miconazole treatment. We also confirmed the autophagy-promoting effect of miconazole in the presence of bafilomycin A1 (Baf A1). The result indicates that a combination treatment of miconazole and Baf A1 improved LC3-II processing, confirming that miconazole promoted autophagic flux. The acridine orange, Lysotracker, and cathepsin D staining results indicate that miconazole increased lysosome formation, revealing its autophagy-promoting function. Finally, miconazole and autophagy inhibitor 3-methyladenine cotreatment further reduced the cell viability and induced apoptosis in BC cells, proving that miconazole provokes protective autophagy in BC cells. Our findings approve that miconazole has an antitumor effect in promoting cell apoptosis; however, its function of protective autophagy is needed to be concerned in cancer treatment.
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Affiliation(s)
- Chao-Yen Ho
- Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - An-Chen Chang
- Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Chung-Hua Hsu
- Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Te-Fu Tsai
- Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
- Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan
| | - Yi-Chia Lin
- Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
- Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan
| | - Kuang-Yu Chou
- Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
- Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan
| | - Hung-En Chen
- Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Ji-Fan Lin
- Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
| | - Po-Chun Chen
- Translational Medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
- Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Thomas I-Sheng Hwang
- Division of Urology, Department of Surgery, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
- Division of Urology, School of Medicine, Fu-Jen Catholic University, New Taipei, Taiwan
- Department of Urology, Taipei Medical University, Taipei, Taiwan
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Kwon I, Song W, Jang Y, Choi MD, Vinci DM, Lee Y. Elevation of hepatic autophagy and antioxidative capacity by endurance exercise is associated with suppression of apoptosis in mice. Ann Hepatol 2021; 19:69-78. [PMID: 31611063 DOI: 10.1016/j.aohep.2019.08.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 08/16/2019] [Accepted: 08/18/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Endurance exercise (EXE) has emerged as a potent inducer of autophagy essential in maintaining cellular homeostasis in various tissues; however, the functional significance and molecular mechanisms of EXE-induced autophagy in the liver remain unclear. Thus, the aim of this study is to examine the signaling nexus of hepatic autophagy pathways occurring during acute EXE and a potential crosstalk between autophagy and apoptosis. MATERIALS AND METHODS C57BL/6 male mice were randomly assigned to sedentary control group (CON, n=9) and endurance exercise (EXE, n=9). Mice assigned to EXE were gradually acclimated to treadmill running and ran for 60min per day for five consecutive days. RESULTS Our data showed that EXE promoted hepatic autophagy via activation of canonical autophagy signaling pathways via mediating microtubule-associated protein B-light chain 3 II (LC3-II), autophagy protein 7 (ATG7), phosphorylated adenosine mono phosphate-activated protein kinase (p-AMPK), CATHEPSIN L, lysosome-associated membrane protein 2 (LAMP2), and a reduction in p62. Interestingly, this autophagy promotion concurred with enhanced anabolic activation via AKT-mammalian target of rapamycin (mTOR)-p70S6K signaling cascade and enhanced antioxidant capacity such as copper zinc superoxide dismutase (CuZnSOD), glutathione peroxidase (GPX), and peroxiredoxin 3 (PRX3), known to be as antagonists of autophagy. Moreover, exercise-induced autophagy was inversely related to apoptosis in the liver. CONCLUSIONS Our findings indicate that improved autophagy and antioxidant capacity, and potentiated anabolic signaling may be a potent non-pharmacological therapeutic strategy against diverse liver diseases.
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Affiliation(s)
- Insu Kwon
- Molecular and Cellular Exercise Physiology Laboratory, Department of Movement Sciences and Health, Usha Kundu, MD College of Health, University of West Florida, Pensacola, FLUSA
| | - Wankeun Song
- Molecular and Cellular Exercise Physiology Laboratory, Department of Movement Sciences and Health, Usha Kundu, MD College of Health, University of West Florida, Pensacola, FLUSA
| | - Yongchul Jang
- Molecular and Cellular Exercise Physiology Laboratory, Department of Movement Sciences and Health, Usha Kundu, MD College of Health, University of West Florida, Pensacola, FLUSA
| | - Myung D Choi
- Exercise Science, School of Health Sciences, Oakland University, Rochester, MIUSA
| | - Debra M Vinci
- Molecular and Cellular Exercise Physiology Laboratory, Department of Movement Sciences and Health, Usha Kundu, MD College of Health, University of West Florida, Pensacola, FLUSA
| | - Youngil Lee
- Molecular and Cellular Exercise Physiology Laboratory, Department of Movement Sciences and Health, Usha Kundu, MD College of Health, University of West Florida, Pensacola, FLUSA.
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Li W, He P, Huang Y, Li YF, Lu J, Li M, Kurihara H, Luo Z, Meng T, Onishi M, Ma C, Jiang L, Hu Y, Gong Q, Zhu D, Xu Y, Liu R, Liu L, Yi C, Zhu Y, Ma N, Okamoto K, Xie Z, Liu J, He RR, Feng D. Selective autophagy of intracellular organelles: recent research advances. Theranostics 2021; 11:222-256. [PMID: 33391472 PMCID: PMC7681076 DOI: 10.7150/thno.49860] [Citation(s) in RCA: 287] [Impact Index Per Article: 71.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 09/04/2020] [Indexed: 12/11/2022] Open
Abstract
Macroautophagy (hereafter called autophagy) is a highly conserved physiological process that degrades over-abundant or damaged organelles, large protein aggregates and invading pathogens via the lysosomal system (the vacuole in plants and yeast). Autophagy is generally induced by stress, such as oxygen-, energy- or amino acid-deprivation, irradiation, drugs, etc. In addition to non-selective bulk degradation, autophagy also occurs in a selective manner, recycling specific organelles, such as mitochondria, peroxisomes, ribosomes, endoplasmic reticulum (ER), lysosomes, nuclei, proteasomes and lipid droplets (LDs). This capability makes selective autophagy a major process in maintaining cellular homeostasis. The dysfunction of selective autophagy is implicated in neurodegenerative diseases (NDDs), tumorigenesis, metabolic disorders, heart failure, etc. Considering the importance of selective autophagy in cell biology, we systemically review the recent advances in our understanding of this process and its regulatory mechanisms. We emphasize the 'cargo-ligand-receptor' model in selective autophagy for specific organelles or cellular components in yeast and mammals, with a focus on mitophagy and ER-phagy, which are finely described as types of selective autophagy. Additionally, we highlight unanswered questions in the field, helping readers focus on the research blind spots that need to be broken.
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Chao X, Qian H, Wang S, Fulte S, Ding WX. Autophagy and liver cancer. Clin Mol Hepatol 2020; 26:606-617. [PMID: 33053934 PMCID: PMC7641568 DOI: 10.3350/cmh.2020.0169] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 07/31/2020] [Accepted: 08/01/2020] [Indexed: 02/07/2023] Open
Abstract
Autophagy is a highly conserved catabolic process that degrades cytosolic proteins and organelles via formation of autophagosomes that fuse with lysosomes to form autolysosomes, whereby autophagic cargos are degraded. Numerous studies have demonstrated that autophagy plays a critical role in the regulation of liver physiology and homeostasis, and impaired autophagy leads to the pathogenesis of various liver diseases such as viral hepatitis, alcohol associated liver diseases (AALD), non-alcoholic fatty liver diseases (NAFLD), and liver cancer. Recent evidence indicates that autophagy may play a dual role in liver cancer: inhibiting early tumor initiation while promoting progression and malignancy of already formed liver tumors. In this review, we summarized the progress of current understanding of how hepatic viral infection, alcohol consumption and diet-induced fatty liver diseases impair hepatic autophagy. We also discussed how impaired autophagy promotes liver tumorigenesis, and paradoxically how autophagy is required to promote the malignancy and progression of liver cancer. Understanding the molecular mechanisms underlying how autophagy differentially affects liver cancer development and progression may help to design better therapeutic strategies for prevention and treatment of liver cancer.
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Affiliation(s)
- Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Hui Qian
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Shaogui Wang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Sam Fulte
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
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Ahodantin J, Lekbaby B, Bou Nader M, Soussan P, Kremsdorf D. Hepatitis B virus X protein enhances the development of liver fibrosis and the expression of genes associated with epithelial-mesenchymal transitions and tumor progenitor cells. Carcinogenesis 2020; 41:358-367. [PMID: 31175830 DOI: 10.1093/carcin/bgz109] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 05/03/2019] [Accepted: 06/06/2019] [Indexed: 12/24/2022] Open
Abstract
The hepatitis B virus X protein (HBx) has pleiotropic biological effects, which underlies its potential role in cell transformation. However, its involvement in hepatic fibrosis remains unclear. In this study, we wanted to clarify, in vivo, the role of HBx protein in the development of liver fibrosis. Mice transgenic for the full-length HBx (FL-HBx) were used. To create liver fibrosis, FL-HBx transgenic and control mice were chronically exposed to carbon tetrachloride (CCl4). Modulation of the expression of proteins involved in matrix remodeling, hepatic metabolism and epithelial-mesenchymal transition (EMT) were investigated. In transgenic mice, FL-HBx expression potentiates CCl4-induced liver fibrosis with increased expression of proteins involved in matrix remodeling (Collagen1a, α-Sma, PdgfR-β, MMP-13). In FL-HBx transgenic mice, an increase in EMT was observed with a higher transcription of two inflammatory cytokines (TNF-α and TGF-β) and a decrease of glutamine synthetase expression level. This was associated with a sustained cell cycle and hepatocyte polyploidy alteration consistent with p38 and ERK1/2 overactivation, increase of PLK1 transcription, accumulation of SQSTM1/p62 protein and increase expression of Beclin-1. This correlates with a higher expression of tumor progenitor cell markers (AFP, Ly6D and EpCam), indicating a higher risk of progression from fibrosis to hepatocellular carcinoma (HCC) in the presence of FL-HBx protein. In conclusion, our results show that FL-HBx protein enhances the development of liver fibrosis and contributes to the progression of liver disease from chronic hepatitis to HCC.
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Affiliation(s)
- James Ahodantin
- Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (Inserm, UMR1135), Sorbonne Universités, Paris, France.,Centre National de la Recherche Scientifique (CNRS, ERL8255), Institut National de la Santé et de la Recherche Médicale (Inserm, UMR1135), Sorbonne Universités, Paris, France
| | - Bouchra Lekbaby
- Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (Inserm, UMR1135), Sorbonne Universités, Paris, France.,Centre National de la Recherche Scientifique (CNRS, ERL8255), Institut National de la Santé et de la Recherche Médicale (Inserm, UMR1135), Sorbonne Universités, Paris, France
| | - Myriam Bou Nader
- Team Proliferation Stress and Liver Physiopathology, Genome and Cancer, Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale (Inserm), Paris, France.,Sorbonne Unversité, USPC, Paris, France.,Université Paris Descartes, Paris, France.,Université Paris Diderot, Paris, France
| | - Patrick Soussan
- Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (Inserm, UMR1135), Sorbonne Universités, Paris, France.,Centre National de la Recherche Scientifique (CNRS, ERL8255), Institut National de la Santé et de la Recherche Médicale (Inserm, UMR1135), Sorbonne Universités, Paris, France
| | - Dina Kremsdorf
- Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (Inserm, UMR1135), Sorbonne Universités, Paris, France.,Centre National de la Recherche Scientifique (CNRS, ERL8255), Institut National de la Santé et de la Recherche Médicale (Inserm, UMR1135), Sorbonne Universités, Paris, France
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Yu Y, Li C, Liu J, Zhu F, Wei S, Huang Y, Huang X, Qin Q. Palmitic Acid Promotes Virus Replication in Fish Cell by Modulating Autophagy Flux and TBK1-IRF3/7 Pathway. Front Immunol 2020; 11:1764. [PMID: 32849631 PMCID: PMC7419653 DOI: 10.3389/fimmu.2020.01764] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 07/01/2020] [Indexed: 12/23/2022] Open
Abstract
Palmitic acid is the most common saturated fatty acid in animals, plants, and microorganisms. Studies highlighted that palmitic acid plays a significant role in diverse cellular processes and viral infections. Accumulation of palmitic acid was observed in fish cells (grouper spleen, GS) infected with Singapore grouper iridovirus (SGIV). The fluctuated content levels after viral infection suggested that palmitic acid was functional in virus-cell interactions. In order to investigate the roles of palmitic acid in SGIV infection, the effects of palmitic acid on SGIV induced cytopathic effect, expression levels of viral genes, viral proteins, as well as virus production were evaluated. The infection and replication of SGIV were increased after exogenous addition of palmitic acid but suppressed after knockdown of fatty acid synthase (FASN), of which the primary function was to catalyze palmitate synthesis. Besides, the promotion of virus replication was associated with the down-regulating of interferon-related molecules, and the reduction of IFN1 and ISRE promotor activities by palmitic acid. We also discovered that palmitic acid restricted TBK1, but not MDA5-induced interferon immune responses. On the other hand, palmitic acid decreased autophagy flux in GS cells via suppressing autophagic degradation, and subsequently enhanced viral replication. Together, our findings indicate that palmitic acid is not only a negative regulator of TBK1-IRF3/7 pathway, but also a suppressor of autophagic flux. Finally, palmitic acid promotes the replication of SGIV in fish cells.
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Affiliation(s)
- Yepin Yu
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Chen Li
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Jiaxin Liu
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Fengyi Zhu
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Shina Wei
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Youhua Huang
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Xiaohong Huang
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China
| | - Qiwei Qin
- Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou, China.,Guangdong Laboratory for Lingnan Modern Agriculture, Guangzhou, China.,Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
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Ding HG, Li Y, Li XS, Liu XQ, Wang KR, Wen MY, Jiang WQ, Zeng HK. Hypercapnia promotes microglial pyroptosis via inhibiting mitophagy in hypoxemic adult rats. CNS Neurosci Ther 2020; 26:1134-1146. [PMID: 32666671 PMCID: PMC7564198 DOI: 10.1111/cns.13435] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/22/2020] [Accepted: 06/24/2020] [Indexed: 12/19/2022] Open
Abstract
Background Hypoxemia is a typical symptom of acute respiratory distress syndrome. To avoid pulmonary morbidity, low tidal volume ventilation is often applied. The ventilation strategy will certainly cause hypercapnia. This study aimed to explore whether hypercapnia would promote microglial pyroptosis via inhibiting mitophagy in adult rats with hypoxemia. Methods The cerebral oxygen extraction ratio (CERO2) and partial pressure of brain tissue oxygen (PbtO2) in a rat model of hypercapnia/hypoxemia were assessed. The reactive oxygen species (ROS) production and the expression of LC3‐II/I, p62, caspase‐1, gasdermin D‐N domains (GSDMD‐N), IL‐1β, and IL‐18 in microglial cells were detected. Results Hypercapnia decreased the PbtO2 levels of the hypoxic rats, which was further evidenced by the increased levels of CERO2. Expression levels of LC3‐II were reduced, while p62 expression was increased by hypercapnia in hypoxic microglia. Hypercapnia increased the production of ROS and the expression of caspase‐1, GSDMD‐N, IL‐1β, and IL‐18 in hypoxia‐activated microglia. Scavenging ROS inhibited microglial pyroptosis and expression of IL‐1β and IL‐18. Conclusions These results suggest that hypercapnia‐induced mitophagy inhibition may promote pyroptosis and enhance IL‐1β and IL‐18 release in hypoxia‐activated microglia.
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Affiliation(s)
- Hong-Guang Ding
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Ya Li
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,School of Medicine, South China University of Technology, Guangzhou, China
| | - Xu-Sheng Li
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xin-Qiang Liu
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Kang-Rong Wang
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.,Southern Medical University, Guangzhou, China
| | - Miao-Yun Wen
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Wen-Qiang Jiang
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Hong-Ke Zeng
- Department of Emergency and Critical Care Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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Chen S, Li M, Jiang W, Zheng H, Qi LW, Jiang S. The role of Neu1 in the protective effect of dipsacoside B on acetaminophen-induced liver injury. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:823. [PMID: 32793668 PMCID: PMC7396229 DOI: 10.21037/atm-19-3850] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background Pharmacological induction of autophagy can protect against acetaminophen (APAP) induced acute liver failure (ALF) by removing APAP adducts (APAP-AD), but its mechanism is not well understood. Hepatoprotective effect of saponins from traditional Chinese medicine has attracted widespread attention from all over the world. The content of saponins in Lonicerae Flos (Shanyinhua in Chinese) is up to 15–25%. Dipsacoside B (DB) is a common bioactive ingredient of different Shanyinhua, but its hepatoprotective effect and mechanism are still unknown. The present investigation aimed to study the benefit of DB in APAP-induced hepatotoxicity mouse model and different cell model. Methods Mice were treated with DB by intraperitoneal injection 1 h before treated with 500 mg/kg APAP, which caused ALF after 4 h. HepG2 cells were treated with DB for 1 h before treated with 10 mM APAP for 12 h. Hepatotoxicity was assessed via ALT and AST. Neuraminidase 1 (Neu1), lysosomal autophagy marker LC3 and P62 were examined by western blot. Neu1 activity was assayed using its substrate 2-(4-methylumbelliferyl)-D-N-acetylneuraminic acid. Apoptosis level was examined by TUNEL and caspase 3 activity. Molecular docking was used to predict the interaction between DB and protein Neu1. Results Our results demonstrated that pretreatment with 0.5 μM DB (in vitro) and 50 mg/kg DB (in vivo) respectively reversed increased level of AST and ALT induced by APAP. Histopathological examinations showed reduced necrosis and apoptosis in the liver of DB-treated APAP mice. DB promoted the removal of APAP-AD by lysosomal autophagy. These effects were associated with significant decrease in the level of Neuraminidase 1 (Neu1), a negative regulator of lysosomal exocytosis. Molecular docking results showed that DB could bind to Neu1 protein (binding energy =−7.86 kcal/mol). Akt/mTOR-mediated autophagy and inhibition of apoptosis may be the main mechanisms for the hepatoprotective effects of DB in acetaminophen-induced liver injury. Conclusions These data indicate that DB alleviated hepatotoxicity caused by APAP at least in part via Neu1 inhibition, Akt/mTOR pathway is involved in the detoxification effect of DB on acetaminophen-induced hepatotoxicity.
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Affiliation(s)
- Shuang Chen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.,School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Mengzhen Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.,School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Wei Jiang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.,School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Hao Zheng
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.,School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Lian-Wen Qi
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.,School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.,The Clinical Metabolomics Center, China Pharmaceutical University, Nanjing, China
| | - Shujun Jiang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.,School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.,The Clinical Metabolomics Center, China Pharmaceutical University, Nanjing, China
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Ríos-Ocampo WA, Navas MC, Buist-Homan M, Faber KN, Daemen T, Moshage H. Hepatitis C Virus Proteins Core and NS5A Are Highly Sensitive to Oxidative Stress-Induced Degradation after eIF2α/ATF4 Pathway Activation. Viruses 2020; 12:v12040425. [PMID: 32283772 PMCID: PMC7232227 DOI: 10.3390/v12040425] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 04/07/2020] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) infection is accompanied by increased oxidative stress and endoplasmic reticulum stress as a consequence of viral replication, production of viral proteins, and pro-inflammatory signals. To overcome the cellular stress, hepatocytes have developed several adaptive mechanisms like anti-oxidant response, activation of Unfolded Protein Response and autophagy to achieve cell survival. These adaptive mechanisms could both improve or inhibit viral replication, however, little is known in this regard. In this study, we investigate the mechanisms by which hepatocyte-like (Huh7) cells adapt to cellular stress in the context of HCV protein overexpression and oxidative stress. Huh7 cells stably expressing individual HCV (Core, NS3/4A and NS5A) proteins were treated with the superoxide anion donor menadione to induce oxidative stress. Production of reactive oxygen species and activation of caspase 3 were quantified. The activation of the eIF2α/ATF4 pathway and changes in the steady state levels of the autophagy-related proteins LC3 and p62 were determined either by quantitative polymerase chain reaction (qPCR) or Western blotting. Huh7 cells expressing Core or NS5A demonstrated reduced oxidative stress and apoptosis. In addition, phosphorylation of eIF2α and increased ATF4 and CHOP expression was observed with subsequent HCV Core and NS5A protein degradation. In line with these results, in liver biopsies from patients with hepatitis C, the expression of ATF4 and CHOP was confirmed. HCV Core and NS5A protein degradation was reversed by antioxidant treatment or silencing of the autophagy adaptor protein p62. We demonstrated that hepatocyte-like cells expressing HCV proteins and additionally exposed to oxidative stress adapt to cellular stress through eIF2a/ATF4 activation and selective degradation of HCV pro-oxidant proteins Core and NS5A. This selective degradation is dependent on p62 and results in increased resistance to apoptotic cell death induced by oxidative stress. This mechanism may provide a new key for the study of HCV pathology and lead to novel clinically applicable therapeutic interventions.
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Affiliation(s)
- W. Alfredo Ríos-Ocampo
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (M.B.-H.); (K.N.F.); (H.M.)
- Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands;
- Gastrohepatology Group, Medicine School, University of Antioquia, Medellin 050010, Colombia;
- Correspondence: ; Tel.: +31-50-361-2364 or +31-638-955-716
| | - María-Cristina Navas
- Gastrohepatology Group, Medicine School, University of Antioquia, Medellin 050010, Colombia;
| | - Manon Buist-Homan
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (M.B.-H.); (K.N.F.); (H.M.)
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (M.B.-H.); (K.N.F.); (H.M.)
| | - Toos Daemen
- Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands;
| | - Han Moshage
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands; (M.B.-H.); (K.N.F.); (H.M.)
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Georgila K, Gounis M, Havaki S, Gorgoulis VG, Eliopoulos AG. mTORC1-dependent protein synthesis and autophagy uncouple in the regulation of Apolipoprotein A-I expression. Metabolism 2020; 105:154186. [PMID: 32084429 DOI: 10.1016/j.metabol.2020.154186] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 02/10/2020] [Accepted: 02/16/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Apolipoprotein A-I (ApoA-I) is involved in reverse cholesterol transport as a major component of HDL, but also conveys anti-thrombotic, anti-oxidative, anti-inflammatory and immune-regulatory properties that are pertinent to its protective roles in cardiovascular, inflammatory and malignant pathologies. Despite the pleiotropy in ApoA-I functions, the regulation of intracellular ApoA-I levels remains poorly explored. METHODS HepG2 hepatoma cells and primary mouse hepatocytes were used as in vitro models to study the impact of genetic and chemical inhibitors of autophagy and the proteasome on ApoA-I by immunoblot, immunofluorescence and electron microscopy. Different growth conditions were implemented in conjunction with mTORC inhibitors to model the influence of nutrient scarcity versus sufficiency on ApoA-I regulation. Hepatic ApoA-I expression was also evaluated in high fat diet-fed mice displaying blockade in autophagy. RESULTS Under nutrient-rich conditions, basal ApoA-I levels in liver cells are sustained by the balancing act of autophagy and of mTORC1-dependent de novo protein synthesis. ApoA-I proteolysis occurs through a canonical autophagic pathway involving Beclin1 and ULK1 and the receptor protein p62/SQSTM1 that targets ApoA-I to autophagosomes. However, upon aminoacid insufficiency, suppression of ApoA-I synthesis prevails, rendering mTORC1 inactivation dispensable for autophagy-mediated ApoA-I proteolysis. CONCLUSION These data underscore the major contribution of post-transcriptional mechanisms to ApoA-I levels which differentially involve mTORC1-dependent signaling to protein synthesis and autophagy, depending on nutrient availability. Given the established role of ApoA-I in HDL-mediated reverse cholesterol transport, this mode of ApoA-I regulation may reflect a hepatocellular response to the organismal requirement for maintenance of cholesterol and lipid reserves under conditions of nutrient scarcity.
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Affiliation(s)
- Konstantina Georgila
- Laboratory of Molecular and Cellular Biology, University of Crete Medical School, Heraklion, Crete, Greece; Department of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Michalis Gounis
- Laboratory of Molecular and Cellular Biology, University of Crete Medical School, Heraklion, Crete, Greece
| | - Sophia Havaki
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Vassilis G Gorgoulis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece; Faculty Institute for Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK
| | - Aristides G Eliopoulos
- Department of Biology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece; Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece.
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Ma X, McKeen T, Zhang J, Ding WX. Role and Mechanisms of Mitophagy in Liver Diseases. Cells 2020; 9:cells9040837. [PMID: 32244304 PMCID: PMC7226762 DOI: 10.3390/cells9040837] [Citation(s) in RCA: 168] [Impact Index Per Article: 33.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 03/23/2020] [Accepted: 03/28/2020] [Indexed: 12/12/2022] Open
Abstract
The mitochondrion is an organelle that plays a vital role in the regulation of hepatic cellular redox, lipid metabolism, and cell death. Mitochondrial dysfunction is associated with both acute and chronic liver diseases with emerging evidence indicating that mitophagy, a selective form of autophagy for damaged/excessive mitochondria, plays a key role in the liver’s physiology and pathophysiology. This review will focus on mitochondrial dynamics, mitophagy regulation, and their roles in various liver diseases (alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced liver injury, hepatic ischemia-reperfusion injury, viral hepatitis, and cancer) with the hope that a better understanding of the molecular events and signaling pathways in mitophagy regulation will help identify promising targets for the future treatment of liver diseases.
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Affiliation(s)
- Xiaowen Ma
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA; (X.M.); (T.M.)
| | - Tara McKeen
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA; (X.M.); (T.M.)
| | - Jianhua Zhang
- Department of Pathology, Division of Molecular Cellular Pathology, University of Alabama at Birmingham, 901 19th street South, Birmingham, AL 35294, USA;
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA; (X.M.); (T.M.)
- Correspondence: ; Tel.: +1-913-588-9813
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50
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Wu T, Yang Q, Chen M, Feng Y. Role of an autophagy/lysosome pathway in NF-κB pathway blocked pancreatic cancer Panc-1 cells. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2020; 13:437-446. [PMID: 32269680 PMCID: PMC7137030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 01/19/2020] [Indexed: 06/11/2023]
Abstract
PURPOSE To investigate the role of an autophagy/lysosome pathway in NF-κB pathway blocked pancreatic cancer Panc-1 cells. METHODS The inhibitory effects of SN50 on pancreatic cancer cell line Panc-1 were detected by MTT assay. After SN50 treatment, autophagy activation was observed by MDC staining and transmission electron microscope (TEM). The expression of light chain 3 (LC3) was detected by immunofluorescence staining. Western blotting analyses were used to detect the expression of apoptosis-related protein p53 and autophagy-related proteins LC3, p62, and Beclin1. RESULTS Panc-1 cell activity was inhibited after SN50 treatment. The inhibition ratios of Panc-1 cells were (25.76±5.53)%, (34.35±4.49)% and (45.22±1.76)% after treatment of SN50 for 6 h, 12 h, and 24 h, and all changes were significant (P<0.05). Western blotting analysis showed that expressions of apoptotic protein p53, autophagic protein LC3, and Beclin 1 were increased, but the expression of p62 was down-regulated in Panc-1 cells. After SN50 treatment, immunofluorescence showed staining of microtubule-related protein 1 LC3, and MDC fluorescence staining showed increased autophagy bubbles labeled with MDC. Transmission electron microscope (TEM) was used to observe ultrastructure of Panc-1 cells that underwent autophagy after SN50 treatment. CONCLUSION The activation of NF-κB was blocked by the inhibitor of p65 nuclear translocation, which activated autophagy and induced autophagic cell death in pancreatic cancer Panc-1 cell line.
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Affiliation(s)
- Ting Wu
- Department of Pathology, The Affiliated People’s Hospital of Jiangsu UniversityZhenjiang 212000, Jiangsu Province, China
| | - Qi Yang
- Department of Pathology, Zhenjiang Hospital of Chinese Traditional and Western MedicineZhenjiang 212002, Jiangsu Province, China
| | - Miao Chen
- Department of Pathology, The Affiliated People’s Hospital of Jiangsu UniversityZhenjiang 212000, Jiangsu Province, China
| | - Yizhong Feng
- Department of Pathology, The Second Affiliated Hospital of Soochow UniversitySuzhou 215006, Jiangsu Province, China
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