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Zhang X, Huang L, Liu Y, Li X, Zhou H, Qin K, Li S, Ren S, Jia X, Gao Z. Potential threat of environmental toxin palytoxin to cerebral nerves: A mechanism study in vitro and in vivo. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 295:118150. [PMID: 40199091 DOI: 10.1016/j.ecoenv.2025.118150] [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: 02/02/2025] [Revised: 03/19/2025] [Accepted: 04/02/2025] [Indexed: 04/10/2025]
Abstract
Palytoxin (PTX), a toxin naturally synthesized by marine organisms like Palythoa, Ostreopsis and Trichodesmium spp. in tropical and temperate seas, bioaccumulates in fish and crustaceans, thereby exposing humans through the food chain. Although growing evidence highlights PTX's lethal hepatotoxicity, nephrotoxicity, and cardiotoxicity, its neurotoxic effects and the underlying mechanisms remain elusive. In this study, we assessed the cerebral neurotoxicity of PTX by using HT22 neuronal cells and a chronic mouse model, conducting a comprehensive analysis of phenotypic alterations and gene expression changes. Phenotypic analysis revealed significant damage to mitochondria, endoplasmic reticulum, and axons and disruptions in energy metabolism in PTX-treated neuronal cells and mouse brains. Transcriptome sequencing and real-time quantitative reverse transcription polymerase chain reaction indicated that key genes in the JNK/p38 MAPK signaling, mitochondrial stress, and endoplasmic reticulum stress pathways were significantly altered. Furthermore, pretreatment with JNK and p38 inhibitors significantly restored mitochondrial membrane potential, ATP content, and cell viability, while reducing the expression of pro-apoptotic genes in HT22 cells. These findings confirm that JNK/p38 MAPK signaling pathways activation, leading to mitochondrial stress, is a major contributor to PTX-induced neuronal cell death at the cellular level. Chronic exposure to PTX was shown to damage mammalian cerebral nerves, carrying a potential risk for neurodegenerative diseases. Our study provides insights into the environmental and health risks associated with PTX exposure and offers a foundation for risk assessment and intervention strategies.
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Affiliation(s)
- Xue Zhang
- Tianjin Key Laboratory of Risk Assessment and Control Technology for Environment and Food Safety, Military Medical Sciences Academy, Academy of Military Sciences, Tianjin 300050, China.
| | - Lei Huang
- School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai 200093, China.
| | - Yinliang Liu
- Tianjin Key Laboratory of Risk Assessment and Control Technology for Environment and Food Safety, Military Medical Sciences Academy, Academy of Military Sciences, Tianjin 300050, China.
| | - Xuewen Li
- Department of General Practice Characteristic Medical Center of Chinese People Armed Police Force, Tianjin 300300, China.
| | - Huanying Zhou
- Tianjin Key Laboratory of Risk Assessment and Control Technology for Environment and Food Safety, Military Medical Sciences Academy, Academy of Military Sciences, Tianjin 300050, China.
| | - Kang Qin
- Tianjin Key Laboratory of Risk Assessment and Control Technology for Environment and Food Safety, Military Medical Sciences Academy, Academy of Military Sciences, Tianjin 300050, China.
| | - Shuang Li
- Tianjin Key Laboratory of Risk Assessment and Control Technology for Environment and Food Safety, Military Medical Sciences Academy, Academy of Military Sciences, Tianjin 300050, China.
| | - Shuyue Ren
- Tianjin Key Laboratory of Risk Assessment and Control Technology for Environment and Food Safety, Military Medical Sciences Academy, Academy of Military Sciences, Tianjin 300050, China.
| | - Xuexia Jia
- Tianjin Key Laboratory of Risk Assessment and Control Technology for Environment and Food Safety, Military Medical Sciences Academy, Academy of Military Sciences, Tianjin 300050, China.
| | - Zhixian Gao
- Tianjin Key Laboratory of Risk Assessment and Control Technology for Environment and Food Safety, Military Medical Sciences Academy, Academy of Military Sciences, Tianjin 300050, China.
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Nghiem THT, Nguyen KA, Kusuma F, Park S, Park J, Joe Y, Han J, Chung HT. The PERK-eIF2α-ATF4 Axis Is Involved in Mediating ER-Stress-Induced Ferroptosis via DDIT4-mTORC1 Inhibition and Acetaminophen-Induced Hepatotoxicity. Antioxidants (Basel) 2025; 14:307. [PMID: 40227255 PMCID: PMC11939615 DOI: 10.3390/antiox14030307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 02/24/2025] [Accepted: 02/28/2025] [Indexed: 04/15/2025] Open
Abstract
Ferroptosis, a regulated form of cell death characterized by lipid peroxidation and iron accumulation, is increasingly recognized for its role in disease pathogenesis. The unfolded protein response (UPR) has been implicated in both endoplasmic reticulum (ER) stress and ferroptosis-mediated cell fate decisions; yet, the specific mechanism remains poorly understood. In this study, we demonstrated that ER stress induced by tunicamycin and ferroptosis triggered by erastin both activate the UPR, leading to the induction of ferroptotic cell death. This cell death was mitigated by the application of chemical chaperones and a ferroptosis inhibitor. Among the three arms of the UPR, the PERK-eIF2α-ATF4 signaling axis was identified as a crucial mediator in this process. Mechanistically, the ATF4-driven induction of DDIT4 plays a pivotal role, facilitating ferroptosis via the inhibition of the mTORC1 pathway. Furthermore, acetaminophen (APAP)-induced hepatotoxicity was investigated as a model of eIF2α-ATF4-mediated ferroptosis. Our findings reveal that the inhibition of eIF2α-ATF4 or ferroptosis protects against APAP-induced liver damage, underscoring the therapeutic potential of targeting these pathways. Overall, this study not only clarifies the intricate role of the PERK-eIF2α-ATF4 axis in ER-stress-and erastin-induced ferroptosis but also extends these findings to a clinically relevant model, providing a foundation for potential therapeutic interventions in conditions characterized by dysregulated ferroptosis and ER stress.
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Affiliation(s)
- Thu-Hang Thi Nghiem
- Department of Biological Sciences, University of Ulsan, Ulsan 44610, Republic of Korea;
| | - Kim Anh Nguyen
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan 31151, Republic of Korea; (K.A.N.); (F.K.); (S.P.)
| | - Fedho Kusuma
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan 31151, Republic of Korea; (K.A.N.); (F.K.); (S.P.)
| | - Soyoung Park
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan 31151, Republic of Korea; (K.A.N.); (F.K.); (S.P.)
| | - Jeongmin Park
- College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea; (J.P.); (Y.J.)
| | - Yeonsoo Joe
- College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea; (J.P.); (Y.J.)
| | - Jaeseok Han
- Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan 31151, Republic of Korea; (K.A.N.); (F.K.); (S.P.)
- Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan 31151, Republic of Korea
| | - Hun Taeg Chung
- College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea; (J.P.); (Y.J.)
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3
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Karin M, Kim JY. MASH as an emerging cause of hepatocellular carcinoma: current knowledge and future perspectives. Mol Oncol 2025; 19:275-294. [PMID: 38874196 PMCID: PMC11793012 DOI: 10.1002/1878-0261.13685] [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: 07/17/2023] [Revised: 04/15/2024] [Accepted: 06/04/2024] [Indexed: 06/15/2024] Open
Abstract
Hepatocellular carcinoma is one of the deadliest and fastest-growing cancers. Among HCC etiologies, metabolic dysfunction-associated fatty liver disease (MAFLD) has served as a major HCC driver due to its great potential for increasing cirrhosis. The obesogenic environment fosters a positive energy balance and results in a continuous rise of obesity and metabolic syndrome. However, it is difficult to understand how metabolic complications lead to the poor prognosis of liver diseases and which molecular mechanisms are underpinning MAFLD-driven HCC development. Thus, suitable preclinical models that recapitulate human etiologies are essentially required. Numerous preclinical models have been created but not many mimicked anthropometric measures and the course of disease progression shown in the patients. Here we review the literature on adipose tissues, liver-related HCC etiologies and recently discovered genetic mutation signatures found in MAFLD-driven HCC patients. We also critically review current rodent models suggested for MAFLD-driven HCC study.
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Affiliation(s)
- Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of MedicineUniversity of California San DiegoLa JollaCAUSA
| | - Ju Youn Kim
- Department of Molecular and Life ScienceHanyang University ERICAAnsanKorea
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4
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Cheng Z, Chu H, Seki E, Lin R, Yang L. Hepatocyte programmed cell death: the trigger for inflammation and fibrosis in metabolic dysfunction-associated steatohepatitis. Front Cell Dev Biol 2024; 12:1431921. [PMID: 39071804 PMCID: PMC11272544 DOI: 10.3389/fcell.2024.1431921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 06/28/2024] [Indexed: 07/30/2024] Open
Abstract
By replacing and removing defective or infected cells, programmed cell death (PCD) contributes to homeostasis maintenance and body development, which is ubiquitously present in mammals and can occur at any time. Besides apoptosis, more novel modalities of PCD have been described recently, such as necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death. PCD not only regulates multiple physiological processes, but also participates in the pathogenesis of diverse disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is mainly classified into metabolic dysfunction-associated steatotic liver (MASL) and metabolic dysfunction-associated steatohepatitis (MASH), and the latter putatively progresses to cirrhosis and hepatocellular carcinoma. Owing to increased incidence and obscure etiology of MASH, its management still remains a tremendous challenge. Recently, hepatocyte PCD has been attracted much attention as a potent driver of the pathological progression from MASL to MASH, and some pharmacological agents have been proved to exert their salutary effects on MASH partly via the regulation of the activity of hepatocyte PCD. The current review recapitulates the pathogenesis of different modalities of PCD, clarifies the mechanisms underlying how metabolic disorders in MASLD induce hepatocyte PCD and how hepatocyte PCD contributes to inflammatory and fibrotic progression of MASH, discusses several signaling pathways in hepatocytes governing the execution of PCD, and summarizes some potential pharmacological agents for MASH treatment which exert their therapeutic effects partly via the regulation of hepatocyte PCD. These findings indicate that hepatocyte PCD putatively represents a new therapeutic point of intervention for MASH.
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Affiliation(s)
- Zilu Cheng
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huikuan Chu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ekihiro Seki
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Rong Lin
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
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5
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Hemagirri M, Chen Y, Gopinath SCB, Sahreen S, Adnan M, Sasidharan S. Crosstalk between protein misfolding and endoplasmic reticulum stress during ageing and their role in age-related disorders. Biochimie 2024; 221:159-181. [PMID: 37918463 DOI: 10.1016/j.biochi.2023.10.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/25/2023] [Accepted: 10/30/2023] [Indexed: 11/04/2023]
Abstract
Maintaining the proteome is crucial to retaining cell functionality and response to multiple intrinsic and extrinsic stressors. Protein misfolding increased the endoplasmic reticulum (ER) stress and activated the adaptive unfolded protein response (UPR) to restore cell homeostasis. Apoptosis occurs when ER stress is prolonged or the adaptive response fails. In healthy young cells, the ratio of protein folding machinery to quantities of misfolded proteins is balanced under normal circumstances. However, the age-related deterioration of the complex systems for handling protein misfolding is accompanied by ageing-related disruption of protein homeostasis, which results in the build-up of misfolded and aggregated proteins. This ultimately results in decreased cell viability and forms the basis of common age-related diseases called protein misfolding diseases. Proteins or protein fragments convert from their ordinarily soluble forms to insoluble fibrils or plaques in many of these disorders, which build up in various organs such as the liver, brain, or spleen. Alzheimer's, Parkinson's, type II diabetes, and cancer are diseases in this group commonly manifest in later life. Thus, protein misfolding and its prevention by chaperones and different degradation paths are becoming understood from molecular perspectives. Proteodynamics information will likely affect future interventional techniques to combat cellular stress and support healthy ageing by avoiding and treating protein conformational disorders. This review provides an overview of the diverse proteostasis machinery, protein misfolding, and ER stress involvement, which activates the UPR sensors. Here, we will discuss the crosstalk between protein misfolding and ER stress and their role in developing age-related diseases.
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Affiliation(s)
- Manisekaran Hemagirri
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Yeng Chen
- Department of Oral & Craniofacial Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, 50603, Malaysia
| | - Subash C B Gopinath
- Faculty of Chemical Engineering and Technology, Universiti Malaysia Perlis, Arau, 02600, Malaysia
| | - Sumaira Sahreen
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia
| | - Mohd Adnan
- Department of Biology, College of Science, University of Ha'il, Ha'il, P. O. Box 2440, Saudi Arabia.
| | - Sreenivasan Sasidharan
- Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, USM, 11800, Pulau Pinang, Malaysia.
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Li Y, Yang P, Ye J, Xu Q, Wu J, Wang Y. Updated mechanisms of MASLD pathogenesis. Lipids Health Dis 2024; 23:117. [PMID: 38649999 PMCID: PMC11034170 DOI: 10.1186/s12944-024-02108-x] [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: 11/20/2023] [Accepted: 04/11/2024] [Indexed: 04/25/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has garnered considerable attention globally. Changing lifestyles, over-nutrition, and physical inactivity have promoted its development. MASLD is typically accompanied by obesity and is strongly linked to metabolic syndromes. Given that MASLD prevalence is on the rise, there is an urgent need to elucidate its pathogenesis. Hepatic lipid accumulation generally triggers lipotoxicity and induces MASLD or progress to metabolic dysfunction-associated steatohepatitis (MASH) by mediating endoplasmic reticulum stress, oxidative stress, organelle dysfunction, and ferroptosis. Recently, significant attention has been directed towards exploring the role of gut microbial dysbiosis in the development of MASLD, offering a novel therapeutic target for MASLD. Considering that there are no recognized pharmacological therapies due to the diversity of mechanisms involved in MASLD and the difficulty associated with undertaking clinical trials, potential targets in MASLD remain elusive. Thus, this article aimed to summarize and evaluate the prominent roles of lipotoxicity, ferroptosis, and gut microbes in the development of MASLD and the mechanisms underlying their effects. Furthermore, existing advances and challenges in the treatment of MASLD were outlined.
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Affiliation(s)
- Yuxuan Li
- Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Translational Medicine Center, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Peipei Yang
- Translational Medicine Center, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Jialu Ye
- Translational Medicine Center, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China
| | - Qiyuan Xu
- Wenzhou Medical University, Wenzhou, China
| | - Jiaqi Wu
- Translational Medicine Center, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China.
- Department of Gastroenterology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China.
| | - Yidong Wang
- Department of Cardiology, State Key Laboratory of Transvascular Implantation Devices, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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7
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Raza S, Rajak S, Singh R, Zhou J, Sinha RA, Goel A. Cell-type specific role of autophagy in the liver and its implications in non-alcoholic fatty liver disease. World J Hepatol 2023; 15:1272-1283. [PMID: 38192406 PMCID: PMC7615497 DOI: 10.4254/wjh.v15.i12.1272] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/07/2023] [Accepted: 12/08/2023] [Indexed: 12/25/2023] Open
Abstract
Autophagy, a cellular degradative process, has emerged as a key regulator of cellular energy production and stress mitigation. Dysregulated autophagy is a common phenomenon observed in several human diseases, and its restoration offers curative advantage. Non-alcoholic fatty liver disease (NAFLD), more recently renamed metabolic dysfunction-associated steatotic liver disease, is a major metabolic liver disease affecting almost 30% of the world population. Unfortunately, NAFLD has no pharmacological therapies available to date. Autophagy regulates several hepatic processes including lipid metabolism, inflammation, cellular integrity and cellular plasticity in both parenchymal (hepatocytes) and non-parenchymal cells (Kupffer cells, hepatic stellate cells and sinusoidal endothelial cells) with a profound impact on NAFLD progression. Understanding cell type-specific autophagy in the liver is essential in order to develop targeted treatments for liver diseases such as NAFLD. Modulating autophagy in specific cell types can have varying effects on liver function and pathology, making it a promising area of research for liver-related disorders. This review aims to summarize our present understanding of cell-type specific effects of autophagy and their implications in developing autophagy centric therapies for NAFLD.
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Affiliation(s)
- Sana Raza
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Uttar Pradesh, Lucknow 226014, India
| | - Sangam Rajak
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Uttar Pradesh, Lucknow 226014, India
| | - Rajani Singh
- Department of Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Uttar Pradesh, Lucknow 226014, India
| | - Jin Zhou
- CVMD, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Rohit A Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Uttar Pradesh, Lucknow 226014, India
| | - Amit Goel
- Department of Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Uttar Pradesh, Lucknow 226014, India.
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Venkatesan N, Doskey LC, Malhi H. The Role of Endoplasmic Reticulum in Lipotoxicity during Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Pathogenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1887-1899. [PMID: 37689385 PMCID: PMC10699131 DOI: 10.1016/j.ajpath.2023.08.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/14/2023] [Accepted: 08/18/2023] [Indexed: 09/11/2023]
Abstract
Perturbations in lipid and protein homeostasis induce endoplasmic reticulum (ER) stress in metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease. Lipotoxic and proteotoxic stress can activate the unfolded protein response (UPR) transducers: inositol requiring enzyme1α, PKR-like ER kinase, and activating transcription factor 6α. Collectively, these pathways induce expression of genes that encode functions to resolve the protein folding defect and ER stress by increasing the protein folding capacity of the ER and degradation of misfolded proteins. The ER is also intimately connected with lipid metabolism, including de novo ceramide synthesis, phospholipid and cholesterol synthesis, and lipid droplet formation. Following their activation, the UPR transducers also regulate lipogenic pathways in the liver. With persistent ER stress, cellular adaptation fails, resulting in hepatocyte apoptosis, a pathological marker of liver disease. In addition to the ER-nucleus signaling activated by the UPR, the ER can interact with other organelles via membrane contact sites. Modulating intracellular communication between ER and endosomes, lipid droplets, and mitochondria to restore ER homeostasis could have therapeutic efficacy in ameliorating liver disease. Recent studies have also demonstrated that cells can convey ER stress by the release of extracellular vesicles. This review discusses lipotoxic ER stress and the central role of the ER in communicating ER stress to other intracellular organelles in MASLD pathogenesis.
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Affiliation(s)
- Nanditha Venkatesan
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Luke C Doskey
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
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Sun X, Shen J, Perrimon N, Kong X, Wang D. The endoribonuclease Arlr is required to maintain lipid homeostasis by downregulating lipolytic genes during aging. Nat Commun 2023; 14:6254. [PMID: 37803019 PMCID: PMC10558556 DOI: 10.1038/s41467-023-42042-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 09/28/2023] [Indexed: 10/08/2023] Open
Abstract
While disorders in lipid metabolism have been associated with aging and age-related diseases, how lipid metabolism is regulated during aging is poorly understood. Here, we characterize the Drosophila endoribonuclease CG2145, an ortholog of mammalian EndoU that we named Age-related lipid regulator (Arlr), as a regulator of lipid homeostasis during aging. In adult adipose tissues, Arlr is necessary for maintenance of lipid storage in lipid droplets (LDs) as flies age, a phenotype that can be rescued by either high-fat or high-glucose diet. Interestingly, RNA-seq of arlr mutant adipose tissues and RIP-seq suggest that Arlr affects lipid metabolism through the degradation of the mRNAs of lipolysis genes - a model further supported by the observation that knockdown of Lsd-1, regucalcin, yip2 or CG5162, which encode genes involved in lipolysis, rescue the LD defects of arlr mutants. In addition, we characterize DendoU as a functional paralog of Arlr and show that human ENDOU can rescue arlr mutants. Altogether, our study reveals a role of ENDOU-like endonucleases as negative regulator of lipolysis.
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Affiliation(s)
- Xiaowei Sun
- Department of Plant Biosecurity and MARA Key Laboratory of Surveillance and Management for Plant Quarantine Pests, College of Plant Protection, China Agricultural University, Beijing, China
| | - Jie Shen
- Department of Plant Biosecurity and MARA Key Laboratory of Surveillance and Management for Plant Quarantine Pests, College of Plant Protection, China Agricultural University, Beijing, China
| | - Norbert Perrimon
- Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Howard Hughes Medical Institute, Boston, MA, USA
| | - Xue Kong
- Department of Plant Biosecurity and MARA Key Laboratory of Surveillance and Management for Plant Quarantine Pests, College of Plant Protection, China Agricultural University, Beijing, China
| | - Dan Wang
- Department of Plant Biosecurity and MARA Key Laboratory of Surveillance and Management for Plant Quarantine Pests, College of Plant Protection, China Agricultural University, Beijing, China.
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10
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Han S, Jeong S, Ahn JC, Cho Y, Choi S, Park SJ, Kim KH, Lee G, Son JS, Park SM. Association of post-smoking cessation changes in fasting serum glucose with changes in predicted fatty liver score. Sci Rep 2023; 13:10300. [PMID: 37365204 DOI: 10.1038/s41598-023-37194-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 06/17/2023] [Indexed: 06/28/2023] Open
Abstract
Major post-cessation metabolic changes include weight gain and hyperglycemia. However, the association of post-cessation change in fasting serum glucose (FSG) with risk of fatty liver remains unclear. A total of 111,106 participants aged 40 and above who underwent health screening at least once in two examination periods were extracted from the Korean National Health Insurance Service-National Sample Cohort. Fatty liver status was evaluated using the Korean National Health and Nutrition Examination Survey nonalcoholic fatty liver disease (K-NAFLD) score. Linear and logistic regression were used to calculate the adjusted mean (aMean) and adjusted odds ratio (aOR) with 95% confidence intervals. Compared to stable (aMean 0.10; 95% CI 0.03-0.18) and decline (aMean - 0.60; 95% CI - 0.71 to 0.49) groups, FSG elevation (aMean 1.28; 95% CI 1.16-1.39) was associated with higher K-NAFLD score even within different body mass index change groups. Risk of fatty liver was significantly reduced among participants with stable (aOR 0.38; 95% CI 0.31-0.45) and declined (aOR 0.17; 95% CI 0.13-0.22) FSG levels after smoking cessation compared to FSG elevation group. This study suggests that quitters with elevated FSG are associated with higher NAFLD risk and may benefit from careful monitoring of FSG levels and management of other cardiovascular risk factors.
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Affiliation(s)
- Saemi Han
- Department of Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Seogsong Jeong
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea
- Department of Biomedical Informatics, CHA University School of Medicine, Seongnam, South Korea
| | - Joseph C Ahn
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Yoosun Cho
- Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Seulggie Choi
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea
| | - Sun Jae Park
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea
| | - Kyae Hyung Kim
- Department of Family Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Gyeongsil Lee
- KS Health Link Inst. and Life Clinic, Seoul, South Korea
| | - Joung Sik Son
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, South Korea
| | - Sang Min Park
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, South Korea.
- Department of Family Medicine, Seoul National University Hospital, Seoul, South Korea.
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11
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Rahimi S, Angaji SA, Majd A, Hatami B, Baghaei K. Evaluating the effect of basic fibroblast growth factor on the progression of NASH disease by inhibiting ceramide synthesis and ER stress-related pathways. Eur J Pharmacol 2023; 942:175536. [PMID: 36693552 DOI: 10.1016/j.ejphar.2023.175536] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/05/2023] [Accepted: 01/20/2023] [Indexed: 01/22/2023]
Abstract
Non-alcoholic steatohepatitis (NASH) is associated with intrahepatic lipid accumulation, inflammation, and hepatocyte death. Several studies have indicated that high-fat diets increase ceramide synthases-6 (CerS-6) expression and a concomitant elevation of C16-ceramides, which can modulate endoplasmic reticulum (ER) stress and further contribute to the progression of NASH. Ceramide levels have reportedly been impacted by basic fibroblast growth factor (bFGF) in various diseases. This study looked into the role of bFGF on CerS6/C16-ceramide and ER stress-related pathways in a mouse model of NASH. Male C57BL/6J mice were fed a western diet (WD) combined with carbon tetrachloride (CCl4) for eight weeks. Next, bFGF was injected into the NASH mice for seven days of continuous treatment. The effects of bFGF on NASH endpoints (including steatosis, inflammation, ballooning, and fibrosis), ceramide levels and ER-stress-induced inflammation, reactive oxygen species (ROS) production, and apoptosis were evaluated. Treatment with bFGF significantly reduced CerS-6/C16-ceramide. Further, the inflammatory condition was alleviated with reduction of nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6) gene expression. ROS level was also reduced. ER stress-related cell death diminished by reducing C/EBP homologous protein (CHOP) mRNA expression and caspase 3 activity. Furthermore, activation of the hepatic stellate cells was inhibited in the bFGF-treated mice by lowering the amount of alpha-smooth muscle actin (α-SMA) at the mRNA and protein level. According to our findings, CerS-6/C16-ceramide alteration impacts ER stress-mediated inflammation, oxidative stress, and apoptosis. The bFGF treatment effectively attenuated the development of NASH by downregulating CerS-6/C16-ceramide and subsequent ER stress-related pathways.
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Affiliation(s)
- Shahrzad Rahimi
- Department of Genetic, North Tehran Branch, Islamic Azad University, Tehran, 1651153311, Iran
| | - Seyyed Abdolhamid Angaji
- Department of Genetic, North Tehran Branch, Islamic Azad University, Tehran, 1651153311, Iran; Department of Cell and Molecular Biology, Faculty of Biological Science, Kharazmi University, Tehran, 1571914911, Iran
| | - Ahmad Majd
- Department of Biology, North Tehran Branch, Islamic Azad University, Tehran, 1651153311, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, 1985717413, Iran
| | - Kaveh Baghaei
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, 1985717413, Iran; Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, 1985717413, Iran.
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12
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Sinha RA. Autophagy: A Cellular Guardian against Hepatic Lipotoxicity. Genes (Basel) 2023; 14:553. [PMID: 36874473 PMCID: PMC7614268 DOI: 10.3390/genes14030553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 02/16/2023] [Accepted: 02/16/2023] [Indexed: 02/25/2023] Open
Abstract
Lipotoxicity is a phenomenon of lipid-induced cellular injury in nonadipose tissue. Excess of free saturated fatty acids (SFAs) contributes to hepatic injury in nonalcoholic fatty liver disease (NAFLD), which has been growing at an unprecedented rate in recent years. SFAs and their derivatives such as ceramides and membrane phospholipids have been shown to induce intrahepatic oxidative damage and ER stress. Autophagy represents a cellular housekeeping mechanism to counter the perturbation in organelle function and activation of stress signals within the cell. Several aspects of autophagy, including lipid droplet assembly, lipophagy, mitophagy, redox signaling and ER-phagy, play a critical role in mounting a strong defense against lipotoxic lipid species within the hepatic cells. This review provides a succinct overview of our current understanding of autophagy-lipotoxicity interaction and its pharmacological and nonpharmacological modulation in treating NAFLD.
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Affiliation(s)
- Rohit Anthony Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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13
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Liu B, Zhou Y, Wu Q, Fu Y, Zhang X, Wang Z, Yi W, Wang H, Chen Z, Song Z, Xiong W, Qiu Y, He W, Ju Z. EVA1A regulates hematopoietic stem cell regeneration via ER-mitochondria mediated apoptosis. Cell Death Dis 2023; 14:71. [PMID: 36717548 PMCID: PMC9887066 DOI: 10.1038/s41419-023-05559-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 12/27/2022] [Accepted: 01/04/2023] [Indexed: 01/31/2023]
Abstract
Excessive protein synthesis upon enhanced cell proliferation frequently results in an increase of unfolded or misfolded proteins. During hematopoietic regeneration, to replenish the hematopoietic system, hematopoietic stem cells (HSCs) are activated and undergo a rapid proliferation. But how the activated HSCs respond to the proliferation pressure is still ambiguous; The proper control of the functional reservoir in the activated HSCs remains poorly understood. Here, we show a significant upregulation of EVA1A protein associated with the increase of ER stress during hematopoietic regeneration. Deletion of Eva1a significantly enhances the regeneration capacity of HSCs by inhibiting the ER stress-induced apoptosis. Mechanistically, the expression of EVA1A protein was upregulated by CHOP, and thereby promoted the ER-mitochondria interlinking via MCL1, which resulted in mitochondria-mediated apoptosis. These findings reveal a pathway for ER stress responses of HSCs by the EVA1A mediated apoptosis, which play an important role in HSCs regeneration.
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Affiliation(s)
- Bo Liu
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China.
| | - Yuanyuan Zhou
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China
| | - Qiaofeng Wu
- Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, 310036, China
| | - Yuting Fu
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China
| | - Xianli Zhang
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China
| | - Zhenkun Wang
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China
| | - Weiwei Yi
- Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, 310036, China
| | - Hu Wang
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China
- Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, 310036, China
| | - Zhiyang Chen
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China
| | - Zhangfa Song
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China
| | - Wei Xiong
- Hefei National Laboratory for Physical Sciences at the Microscale, Institute on Aging and Brain Disorders, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China
| | - Yugang Qiu
- School of Rehabilitation Medicine, Weifang Medical University, Weifang, 261053, China
| | - Weifeng He
- Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Army Military Medical University, Chongqing, 400038, China.
| | - Zhenyu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou, 510632, China.
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Moutan Cortex Extract Modulates Macrophage Activation via Lipopolysaccharide-Induced Calcium Signaling and ER Stress-CHOP Pathway. Int J Mol Sci 2023; 24:ijms24032062. [PMID: 36768384 PMCID: PMC9916843 DOI: 10.3390/ijms24032062] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/16/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
Moutan Cortex, Paeonia suffruticosa root, has long been used as a medicine for the treatment of inflammatory diseases. The aim of this study was to evaluate the modulative properties of Moutan Cortex water extract (CP) on endoplasmic reticulum (ER) stress-related macrophage activation via the calcium-CHOP pathway. RAW 264.7 mouse macrophages were activated by lipopolysaccharide (LPS), and the levels of various inflammatory mediators from RAW 264.7 were evaluated. The multiplex cytokine assay was used to investigate both cytokines and growth factors, and RT-PCR was used to investigate the expressions of inflammation-related genes, such as CHOP. Data represent the levels of NO and cytosolic calcium in LPS-stimulated RAW 264.7 were significantly inhibited by CP as well as hydrogen peroxide (p < 0.05). Minutely, NO production in LPS-stimulated RAW 264.7 incubated with CP at concentrations of 25, 50, 100, and 200 µg/mL for 24 h was 97.32 ± 1.55%, 95.86 ± 2.26%, 94.64 ± 1.83%, and 92.69 ± 2.31% of the control value (LPS only), respectively (p < 0.05). Calcium release in LPS-stimulated RAW 264.7 incubated with CP at concentrations of 25, 50, 100, and 200 µg/mL for 18 h was 95.78 ± 1.64%, 95.41 ± 1.14%, 94.54 ± 2.76%, and 90.89 ± 3.34% of the control value, respectively (p < 0.05). Hydrogen peroxide production in LPS-stimulated RAW 264.7 incubated with CP at concentrations of 25, 50, 100, and 200 µg/mL for 24 h was 79.15 ± 7.16%, 63.83 ± 4.03%, 46.27 ± 4.38%, and 40.66 ± 4.03% of the control value, respectively (p < 0.05). It is interesting that the production of IL-6, TNF-α, G-CSF, MIP-1α, MIP-2, and M-CSF in LPS-stimulated RAW 264.7 were significantly inhibited by CP (p < 0.05), while the production of LIX, LIF, RANTES, and MIP-1β showed a meaningful decrease. CP at concentrations of 25, 50, 100, and 200 µg/mL significantly reduced the transcription of Chop, Camk2α, NOS, STAT1, STAT3, Ptgs2, Jak2, c-Jun, Fas, c-Fos, TLR3, and TLR9 in LPS-stimulated RAW 264.7 (p < 0.05). CP at concentrations of 25, 50, and 100 µg/mL significantly reduced the phosphorylation of STAT3, p38 MAPK, and IκB-α in LPS-stimulated RAW 264.7 (p < 0.05). These results suggest that CP might modulate macrophage activation via LPS-induced calcium signaling and the ER stress-CHOP pathway.
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Chen Y, Yan X, Wang T, Deng H, Deng X, Xu F, Liang H. PNPLA3 148M/M Is More Susceptible to Palmitic Acid-Induced Endoplasmic Reticulum Stress-Associated Apoptosis in HepG2 Cells. Int J Endocrinol 2023; 2023:2872408. [PMID: 36825197 PMCID: PMC9943609 DOI: 10.1155/2023/2872408] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 11/16/2022] [Accepted: 11/22/2022] [Indexed: 02/16/2023] Open
Abstract
BACKGROUND Patatin-like phospholipase domain-containing 3 (PNPLA3) is a major susceptibility gene for nonalcoholic fatty liver disease (NAFLD), and its rs738409 (I148M) polymorphism is associated with the occurrence and progression of NAFLD. Endoplasmic reticulum (ER) stress-related hepatocyte lipoapoptosis contributes to the progress of NAFLD. PNPLA3 is also known as a member of the calcium-independent phospholipase A2ε family, which can hydrolyze fatty acids to generate lysophosphatidylcholine (LPC) that induces ER stress-related hepatocyte lipoapoptosis. Whether the PNPLA3 risk genotype 148M/M is involved in more severe ER stress-associated lipoapoptosis is unclear. METHODS A PNPLA3148I knock-in HepG2 cell model was constructed based on HepG2 expressing PNPLA3 148M/M using the Cas9/sgRNA system. PNPLA3 148M/M, I/M, and I/I cells were treated with 0.3 mM palmitic acid (PA) for 24 h to induce lipid deposition. Cellular lipid deposition was detected by oil red staining. Apoptosis was observed by TUNEL. LPC was determined by ELISA, and the expression of PNPLA3, the ER stress marker Bip, molecules involved in the ER stress PERK/elF-2a pathway, and its downstream C/EBP homologous protein (CHOP)-mediated apoptotic pathway were detected by western blot. RESULTS The results showed no difference in PNPLA3 basal expression and basal hepatocyte lipid content between the three genotypes of cells. Lipid deposition and apoptosis were more severe in PNPLA3 148M/M and 148I/M cells than in I/I cells after PA treatment. PA-induced upregulation of protein expression of Bip, ER stress-responsive PERK pathway molecules p-PERK, p-eIF2α, CHOP, and CHOP-associated apoptotic molecules PUMA and Bax were more pronounced in PNPLA3 148M/M cells than in PNPLA3 148I/I cells. The basal LPC levels and the PA-treated increase of LPC levels in the cell culture supernatants did not differ between the three genotypic cells. CONCLUSION PNPLA3 148M/M cells were more susceptible to PA-induced lipid deposition and ER stress-related apoptosis than 148I/I cells, and the proapoptotic susceptibility of PNPLA3 148M/M is independent of LPC.
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Affiliation(s)
- Yunzhi Chen
- Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
- Guangdong Provincial People's Hospital, Guangzhou 510080, China
| | - Xuemei Yan
- Department of Endocrinology and Metabolism, Joint Service Support Force 903 Hospital, Hangzhou 310005, China
| | - Tian Wang
- Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Hongrong Deng
- Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Xiaojie Deng
- Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Fen Xu
- Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Hua Liang
- Department of Endocrinology and Metabolism, Third Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
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16
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Zheng W, Sun Q, Li L, Cheng Y, Chen Y, Lv M, Xiang X. Role of endoplasmic reticulum stress in hepatic glucose and lipid metabolism and therapeutic strategies for metabolic liver disease. Int Immunopharmacol 2022; 113:109458. [DOI: 10.1016/j.intimp.2022.109458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/22/2022] [Accepted: 11/10/2022] [Indexed: 11/18/2022]
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17
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Pan J, Li X, Liu H, Wang C, Xu S, Xu B, Deng Y, Yang T, Liu W. Exploring the molecular mechanisms underlie the endoplasmic reticulum stress-mediated methylmercury-induced neuronal developmental damage. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 245:114099. [PMID: 36152427 DOI: 10.1016/j.ecoenv.2022.114099] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 09/01/2022] [Accepted: 09/16/2022] [Indexed: 06/16/2023]
Abstract
Methylmercury (MeHg) is a ubiquitous environmental pollutant, which can cross the placenta and blood brain barrier, thus affecting fetal growth and development. Although previous studies have demonstrated that MeHg induces endoplasmic reticulum (ER) stress in rat cerebral cortex and primary neurons, the role of ER stress in MeHg-induced neurodevelopmental toxicity remains unclear. Here, we used ICR pregnant mice and hippocampal neurons cells (HT22 cells) to investigate the molecular mechanism by which MeHg exposure during pregnancy affects neurodevelopment. We found that prenatal MeHg exposure caused developmental delay in offspring, accompanied with ER stress, cell apoptosis, cell cycle arrest and abnormal DNA methylation. Then, we used ER stress specific inhibitor 4-PBA and CHOP siRNA to investigate the role of ER stress on HT22 cells damage caused by MeHg. The results showed that 4-PBA pretreatment restored MeHg-induced axonal shortening and alleviated apoptosis, cell cycle arrest and DNA methylation. At the same time, the activation of CHOP/c-Jun/GADD45A signaling pathway was inhibited, and the interaction between CHOP and c-Jun was weakened. In addition, CHOP siRNA reduced the expression of c-Jun and GADD45A, and relieved DNA methylation levels to some extent. In summary, our study suggested that ER stress induced by MeHg mediated cell apoptosis and cell cycle arrest, and may affect DNA methylation through activation of CHOP/c-Jun/GADD45A signaling pathway, thus leading to neuronal damage.
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Affiliation(s)
- Jingjing Pan
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Xiaoyang Li
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Haihui Liu
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Chen Wang
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Si Xu
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Bin Xu
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Yu Deng
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Tianyao Yang
- Department of Environmental Health, School of Public Health, China Medical University, China
| | - Wei Liu
- Department of Environmental Health, School of Public Health, China Medical University, China.
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18
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Cocoa Extract Provides Protection against 6-OHDA Toxicity in SH-SY5Y Dopaminergic Neurons by Targeting PERK. Biomedicines 2022; 10:biomedicines10082009. [PMID: 36009556 PMCID: PMC9405838 DOI: 10.3390/biomedicines10082009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 08/12/2022] [Accepted: 08/15/2022] [Indexed: 11/17/2022] Open
Abstract
Parkinson’s disease (PD) represents one of the most common neurodegenerative disorders, characterized by a dopamine (DA) deficiency in striatal synapses and misfolded toxic α-synuclein aggregates with concomitant cytotoxicity. In this regard, the misfolded proteins accumulation in neurodegenerative disorders induces a remarkable perturbations of endoplasmic reticulum (ER) homeostasis leading to persistent ER stress, which in turn, effects protein synthesis, modification, and folding quality control. A large body of evidence suggests that natural products target the ER stress signaling pathway, exerting a potential action in cancers, diabetes, cardiovascular and neurodegenerative diseases. This study aims to assess the neuroprotective effect of cocoa extract and its purified fractions against a cellular model of Parkinson’s disease represented by 6-hydroxydopamine (6-OHDA)-induced SH-SY5Y human neuroblastoma. Our findings demonstrate, for the first time, the ability of cocoa to specifically targets PERK sensor, with significant antioxidant and antiapoptotic activities as both crude and fractioning extracts. In addition, cocoa also showed antiapoptotic properties in 3D cell model and a notable ability to inhibit the accumulation of α-synuclein in 6-OHDA-induced cells. Overall, these results indicate that cocoa exerts neuroprotective effects suggesting a novel possible strategy to prevent or, at least, mitigate neurodegenerative disorders, such as PD.
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19
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Xu X, Poulsen KL, Wu L, Liu S, Miyata T, Song Q, Wei Q, Zhao C, Lin C, Yang J. Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Signal Transduct Target Ther 2022; 7:287. [PMID: 35963848 PMCID: PMC9376100 DOI: 10.1038/s41392-022-01119-3] [Citation(s) in RCA: 178] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/15/2022] [Accepted: 07/08/2022] [Indexed: 11/24/2022] Open
Abstract
Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut-liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH.
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Affiliation(s)
- Xiaohan Xu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Kyle L Poulsen
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Lijuan Wu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Shan Liu
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Tatsunori Miyata
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Qiaoling Song
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Qingda Wei
- School of Medicine, Zhengzhou University, Zhengzhou, China
| | - Chenyang Zhao
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Chunhua Lin
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jinbo Yang
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
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Hussain Y, Khan H, Efferth T, Alam W. Regulation of endoplasmic reticulum stress by hesperetin: Focus on antitumor and cytoprotective effects. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 100:153985. [PMID: 35358935 DOI: 10.1016/j.phymed.2022.153985] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 10/14/2021] [Accepted: 02/10/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Cancer is still an all-times issue due to a large and even increasing number of deaths. Impaired genes regulating cell proliferation and apoptosis are targets for the development of novel cancer treatments. HYPOTHESIS Increased transcription of NADPH oxidase activator (NOXA), Bcl2-like11 (BIM), BH3-only proteins and p53 unregulated apoptosis modulator (PUMA) is caused by the imbalance between pro- and anti-apoptotic Bcl-2 proteins due to endoplasmic reticulum (ER) stress. The membranous network of ER is present in all eukaryotic cells. ER stress facilitates the interaction between Bax and PUMA, triggering the release of cytochrome C. As a main intracellular organelle, ER is responsible for translocation as well as post-translation modification and protein folding. RESULTS Hesperetin is a cytoprotective flavonone, which acts against ER stress and protects from cell damage induced by reactive oxygen species (ROS) and reactive nitrogen species (RNS). Hesperetin inhibits lipid peroxidation induced by Fe2+ and l-ascorbic acid in rat brain homogenates. CONCLUSION This review deals with the anticancer effects of hesperetin regarding the regulation of ER stress as a principal mechanism in the pathogenesis of tumors.
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Affiliation(s)
- Yaseen Hussain
- College of Pharmaceutical Sciences, Soochow University, 215123, China
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, 23200, Pakistan.
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany.
| | - Waqas Alam
- Department of Pharmacy, Abdul Wali Khan University Mardan, 23200, Pakistan
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Tang M, Zheng Y, Li J, Hu Y. The X box binding protein 1/C/EBP homologous protein pathway induces apoptosis of endothelial cells under hyperglycemia. Exp Ther Med 2022; 24:454. [PMID: 35720621 DOI: 10.3892/etm.2022.11381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 06/16/2021] [Indexed: 11/06/2022] Open
Affiliation(s)
- Maoshun Tang
- Department of Neurosurgery, Shenzhen Hospital, University of Chinese Academy of Sciences, Shenzhen, Guangdong 518106, P.R. China
| | - Yi Zheng
- Department of Science and Education, Shenzhen Hospital, University of Chinese Academy of Sciences, Shenzhen, Guangdong 518106, P.R. China
| | - Jianping Li
- Department of Cardiology, Shenzhen Hospital, University of Chinese Academy of Sciences, Shenzhen, Guangdong 518106, P.R. China
| | - Yuanlang Hu
- Department of Obstetrics and Gynecology, Shenzhen Hospital, University of Chinese Academy of Sciences, Shenzhen, Guangdong 518106, P.R. China
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22
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McPhee MJ, Salsman J, Foster J, Thompson J, Mathavarajah S, Dellaire G, Ridgway ND. Running 'LAPS' Around nLD: Nuclear Lipid Droplet Form and Function. Front Cell Dev Biol 2022; 10:837406. [PMID: 35178392 PMCID: PMC8846306 DOI: 10.3389/fcell.2022.837406] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/10/2022] [Indexed: 12/12/2022] Open
Abstract
The nucleus harbours numerous protein subdomains and condensates that regulate chromatin organization, gene expression and genomic stress. A novel nuclear subdomain that is formed following exposure of cells to excess fatty acids is the nuclear lipid droplet (nLD), which is composed of a neutral lipid core surrounded by a phospholipid monolayer and associated regulatory and lipid biosynthetic enzymes. While structurally resembling cytoplasmic LDs, nLDs are formed by distinct but poorly understood mechanisms that involve the emergence of lipid droplets from the lumen of the nucleoplasmic reticulum and de novo lipid synthesis. Luminal lipid droplets that emerge into the nucleoplasm do so at regions of the inner nuclear membrane that become enriched in promyelocytic leukemia (PML) protein. The resulting nLDs that retain PML on their surface are termed lipid-associated PML structures (LAPS), and are distinct from canonical PML nuclear bodies (NB) as they lack key proteins and modifications associated with these NBs. PML is a key regulator of nuclear signaling events and PML NBs are sites of gene regulation and post-translational modification of transcription factors. Therefore, the subfraction of nLDs that form LAPS could regulate lipid stress responses through their recruitment and retention of the PML protein. Both nLDs and LAPS have lipid biosynthetic enzymes on their surface suggesting they are active sites for nuclear phospholipid and triacylglycerol synthesis as well as global lipid regulation. In this review we have summarized the current understanding of nLD and LAPS biogenesis in different cell types, their structure and composition relative to other PML-associated cellular structures, and their role in coordinating a nuclear response to cellular overload of fatty acids.
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Affiliation(s)
- Michael J McPhee
- Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS, Canada
| | - Jayme Salsman
- Department of Pathology, Dalhousie University, Halifax, NS, Canada
| | - Jason Foster
- Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS, Canada
| | - Jordan Thompson
- Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS, Canada
| | | | - Graham Dellaire
- Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS, Canada.,Department of Pathology, Dalhousie University, Halifax, NS, Canada
| | - Neale D Ridgway
- Department of Biochemistry & Molecular Biology, Dalhousie University, Halifax, NS, Canada.,Department of Pediatrics, Dalhousie University, Halifax, NS, Canada
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23
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Duwaerts CC, Maiers JL. ER Disposal Pathways in Chronic Liver Disease: Protective, Pathogenic, and Potential Therapeutic Targets. Front Mol Biosci 2022; 8:804097. [PMID: 35174209 PMCID: PMC8841999 DOI: 10.3389/fmolb.2021.804097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 11/18/2021] [Indexed: 11/13/2022] Open
Abstract
The endoplasmic reticulum is a central player in liver pathophysiology. Chronic injury to the ER through increased lipid content, alcohol metabolism, or accumulation of misfolded proteins causes ER stress, dysregulated hepatocyte function, inflammation, and worsened disease pathogenesis. A key adaptation of the ER to resolve stress is the removal of excess or misfolded proteins. Degradation of intra-luminal or ER membrane proteins occurs through distinct mechanisms that include ER-associated Degradation (ERAD) and ER-to-lysosome-associated degradation (ERLAD), which includes macro-ER-phagy, micro-ER-phagy, and Atg8/LC-3-dependent vesicular delivery. All three of these processes are critical for removing misfolded or unfolded protein aggregates, and re-establishing ER homeostasis following expansion/stress, which is critical for liver function and adaptation to injury. Despite playing a key role in resolving ER stress, the contribution of these degradative processes to liver physiology and pathophysiology is understudied. Analysis of publicly available datasets from diseased livers revealed that numerous genes involved in ER-related degradative pathways are dysregulated; however, their roles and regulation in disease progression are not well defined. Here we discuss the dynamic regulation of ER-related protein disposal pathways in chronic liver disease and cell-type specific roles, as well as potentially targetable mechanisms for treatment of chronic liver disease.
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Affiliation(s)
- Caroline C. Duwaerts
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Jessica L. Maiers
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
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24
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Kalimuthu K, Kim JH, Park YS, Luo X, Zhang L, Ku JL, Choudry MHA, Lee YJ. Glucose deprivation-induced endoplasmic reticulum stress response plays a pivotal role in enhancement of TRAIL cytotoxicity. J Cell Physiol 2021; 236:6666-6677. [PMID: 33586156 PMCID: PMC11572546 DOI: 10.1002/jcp.30329] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 02/02/2021] [Accepted: 02/04/2021] [Indexed: 12/12/2022]
Abstract
Abnormalities of the tumor vasculature result in insufficient blood supply and development of a tumor microenvironment that is characterized by low glucose concentrations, low extracellular pH, and low oxygen tensions. We previously reported that glucose-deprived conditions induce metabolic stress and promote tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cytotoxicity. In this study, we examined whether the metabolic stress-associated endoplasmic reticulum (ER) stress response pathway plays a pivotal role in the enhancement of TRAIL cytotoxicity. We observed no significant cytotoxicity when human colorectal cancer SW48 cells were treated with various doses of TRAIL (2-100 ng/ml) for 4 h or glucose (0-25 mM) for 24 h. However, a combination of TRAIL and low glucose-induced dose-dependent apoptosis through activation of caspases (-8, -9, and -3). Studies with activating transcription factor 4 (ATF4), C/EBP-homologous protein (CHOP), p53 upregulated modulator of apoptosis (PUMA), or death receptor 5 (DR5)-deficient mouse embryonic fibroblasts or HCT116 cells suggest that the ATF4-CHOP-PUMA axis and the ATF4-CHOP-DR5 axis are involved in the combined treatment-induced apoptosis. Moreover, the combined treatment-induced apoptosis was completely suppressed in BH3 interacting-domain death agonist (Bid)- or Bcl-2-associated X protein (Bax)-deficient HCT116 cells, but not Bak-deficient HCT116 cells. Interestingly, the combined treatment-induced Bax oligomerization was suppressed in PUMA-deficient HCT116 cells. These results suggest that glucose deprivation enhances TRAIL-induced apoptosis by integrating the ATF4-CHOP-PUMA axis and the ATF4-CHOP-DR5 axis, consequently amplifying the Bid-Bax-associated mitochondria-dependent pathway.
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Affiliation(s)
- Kalishwaralal Kalimuthu
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Jin Hong Kim
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Yong Seok Park
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Xu Luo
- Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Lin Zhang
- Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Ja-Lok Ku
- Department of Biomedical Sciences/Department of Medicine, Laboratory of Cell Biology, Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Korea
| | - M. Haroon A. Choudry
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Yong J. Lee
- Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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25
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Detection of Unfolded Protein Response by Polymerase Chain Reaction. Methods Mol Biol 2021. [PMID: 34033090 DOI: 10.1007/978-1-0716-1162-3_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
Abstract
The unfolded protein response is a cellular adaptive mechanism localized in the endoplasmic reticulum. It involves three phases: the detection of increased presence of unfolded proteins as a result of cellular stressors; the execution of an adaptive cascade of events aimed at the enhancement of proper protein folding and degradation of improperly folded proteins; and finally, when stress is not alleviated, the execution of programmed cell death. The main effectors of the UPR are transcription factors involved in the upregulation of either chaperone proteins or proapoptotic proteins. Two of these transcription factors are CHOP and the spliced variant of XBP-1 (XBP1s). In this chapter, we describe a quantitative PCR method to detect the upregulation of CHOP and XBP1s mRNA during Tunicamycin-induced UPR.
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Palmitoleate Protects against Zika Virus-Induced Placental Trophoblast Apoptosis. Biomedicines 2021; 9:biomedicines9060643. [PMID: 34200091 PMCID: PMC8226770 DOI: 10.3390/biomedicines9060643] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 05/31/2021] [Indexed: 01/15/2023] Open
Abstract
Zika virus (ZIKV) infection in pregnancy is associated with the development of microcephaly, intrauterine growth restriction, and ocular damage in the fetus. ZIKV infection of the placenta plays a crucial role in the vertical transmission from the maternal circulation to the fetus. Our previous study suggested that ZIKV induces endoplasmic reticulum (ER) stress and apoptosis of placental trophoblasts. Here, we showed that palmitoleate, an omega-7 monounsaturated fatty acid, prevents ZIKV-induced ER stress and apoptosis in placental trophoblasts. Human trophoblast cell lines (JEG-3 and JAR) and normal immortalized trophoblasts (HTR-8) were used. We observed that ZIKV infection of the trophoblasts resulted in apoptosis and treatment of palmitoleate to ZIKV-infected cells significantly prevented apoptosis. However, palmitate (saturated fatty acid) did not offer protection from ZIKV-induced ER stress and apoptosis. We also observed that the Zika viral RNA copies were decreased, and the cell viability improved in ZIKV-infected cells treated with palmitoleate as compared to the infected cells without palmitoleate treatment. Further, palmitoleate was shown to protect against ZIKV-induced upregulation of ER stress markers, C/EBP homologous protein and X-box binding protein-1 splicing in placental trophoblasts. In conclusion, our studies suggest that palmitoleate protects placental trophoblasts against ZIKV-induced ER stress and apoptosis.
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Li M. The role of P53 up-regulated modulator of apoptosis (PUMA) in ovarian development, cardiovascular and neurodegenerative diseases. Apoptosis 2021; 26:235-247. [PMID: 33783663 PMCID: PMC8197724 DOI: 10.1007/s10495-021-01667-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/14/2021] [Indexed: 12/14/2022]
Abstract
P53 up-regulated modulator of apoptosis (PUMA), a pro-apoptotic BCL-2 homology 3 (BH3)-only member of the BCL-2 family, is a direct transcriptional target of P53 that elicits mitochondrial apoptosis under treatment with radiation and chemotherapy. It also induces excessive apoptosis in cardiovascular and/or neurodegenerative diseases. PUMA has been found to play a critical role in ovarian apoptosis. In the present paper, we review the progress of the study in PUMA over the past two decades in terms of its inducement and/or amplification of programmed cell death and describe recent updates to the understanding of both P53-dependent and P53-independent PUMA-mediated apoptotic pathways that are implicated in physiology and pathology, including the development of the ovary and cardiovascular and neurodegenerative diseases. We propose that PUMA may be a key regulator during ovary development, provide a model for PUMA-mediated apoptotic pathways, including intrinsic and extrinsic apoptotic pathways.
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Affiliation(s)
- Mei Li
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science and Technology, Nanjing Agricultural University, 1 Weigang, Nanjing, 210095, China.
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28
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N- trans-Feruloyloctopamine Wakes Up BBC3, DDIT3, CDKN1A, and NOXA Signals to Accelerate HCC Cell Apoptosis. ACTA ACUST UNITED AC 2021; 2021:1560307. [PMID: 34123711 PMCID: PMC8166497 DOI: 10.1155/2021/1560307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 05/11/2021] [Indexed: 12/24/2022]
Abstract
N-trans-Feruloyloctopamine (FO), a natural compound, was reported in our previous study to inhibit a tumor cell malignant phenotype by AKT- and EMT-related signals and might be used as a promising drug for HCC treatment. However, the specific targets and detailed mechanisms still need to be clarified. Screening with RNA-Seq in Huh7 cells treated with FO revealed that 317 genes were modulated, of which 188 genes were upregulated and 129 genes were downregulated. Real-time cell analyzer and flow cytometry data reveal that tumor cell proliferation and apoptosis were impacted by FO. DAVID bioinformatic data showed that most of the biological process GO terms are related to proliferation and apoptosis. KEGG enrichment analysis showed that FO mainly regulates PI3K-AKT- and apoptosis-related signals, in which BBC3, DDIT3, NOXA, and CDKN1A on the surface serve as the novel targets of FO inducing HCC cell apoptosis. The result implied that FO might exacerbate HCC cell apoptosis by regulating BBC3, DDIT3, CDKN1A, and NOXA signals. The obstacle effect of FO can provide new targets and new credibility for the treatment of liver cancer.
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29
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Amorim R, Simões ICM, Veloso C, Carvalho A, Simões RF, Pereira FB, Thiel T, Normann A, Morais C, Jurado AS, Wieckowski MR, Teixeira J, Oliveira PJ. Exploratory Data Analysis of Cell and Mitochondrial High-Fat, High-Sugar Toxicity on Human HepG2 Cells. Nutrients 2021; 13:nu13051723. [PMID: 34069635 PMCID: PMC8161147 DOI: 10.3390/nu13051723] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 05/06/2021] [Accepted: 05/17/2021] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH), one of the deleterious stages of non-alcoholic fatty liver disease, remains a significant cause of liver-related morbidity and mortality worldwide. In the current work, we used an exploratory data analysis to investigate time-dependent cellular and mitochondrial effects of different supra-physiological fatty acids (FA) overload strategies, in the presence or absence of fructose (F), on human hepatoma-derived HepG2 cells. We measured intracellular neutral lipid content and reactive oxygen species (ROS) levels, mitochondrial respiration and morphology, and caspases activity and cell death. FA-treatments induced a time-dependent increase in neutral lipid content, which was paralleled by an increase in ROS. Fructose, by itself, did not increase intracellular lipid content nor aggravated the effects of palmitic acid (PA) or free fatty acids mixture (FFA), although it led to an up-expression of hepatic fructokinase. Instead, F decreased mitochondrial phospholipid content, as well as OXPHOS subunits levels. Increased lipid accumulation and ROS in FA-treatments preceded mitochondrial dysfunction, comprising altered mitochondrial membrane potential (ΔΨm) and morphology, and decreased oxygen consumption rates, especially with PA. Consequently, supra-physiological PA alone or combined with F prompted the activation of caspase pathways leading to a time-dependent decrease in cell viability. Exploratory data analysis methods support this conclusion by clearly identifying the effects of FA treatments. In fact, unsupervised learning algorithms created homogeneous and cohesive clusters, with a clear separation between PA and FFA treated samples to identify a minimal subset of critical mitochondrial markers in order to attain a feasible model to predict cell death in NAFLD or for high throughput screening of possible therapeutic agents, with particular focus in measuring mitochondrial function.
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Affiliation(s)
- Ricardo Amorim
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, 3060-197 Cantanhede, Portugal; (R.A.); (C.V.); (A.C.); (R.F.S.); (J.T.)
- CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
- PhD Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, 3004-531 Coimbra, Portugal
| | - Inês C. M. Simões
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland; (I.C.M.S.); (M.R.W.)
| | - Caroline Veloso
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, 3060-197 Cantanhede, Portugal; (R.A.); (C.V.); (A.C.); (R.F.S.); (J.T.)
| | - Adriana Carvalho
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, 3060-197 Cantanhede, Portugal; (R.A.); (C.V.); (A.C.); (R.F.S.); (J.T.)
- PhD Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, 3004-531 Coimbra, Portugal
| | - Rui F. Simões
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, 3060-197 Cantanhede, Portugal; (R.A.); (C.V.); (A.C.); (R.F.S.); (J.T.)
- PhD Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, 3004-531 Coimbra, Portugal
| | - Francisco B. Pereira
- Center for Informatics and Systems, University of Coimbra, Polo II, Pinhal de Marrocos, 3030-290 Coimbra, Portugal;
- Coimbra Polytechnic-ISEC, 3030-190 Coimbra, Portugal
| | - Theresa Thiel
- Mediagnostic, D-72770 Reutlingen, Germany; (T.T.); (A.N.)
| | - Andrea Normann
- Mediagnostic, D-72770 Reutlingen, Germany; (T.T.); (A.N.)
| | - Catarina Morais
- Center for Neuroscience and Cell Biology, Department of Life Sciences, University of Coimbra, Calçada Martim de Freitas, 3000-456 Coimbra, Portugal; (C.M.); (A.S.J.)
| | - Amália S. Jurado
- Center for Neuroscience and Cell Biology, Department of Life Sciences, University of Coimbra, Calçada Martim de Freitas, 3000-456 Coimbra, Portugal; (C.M.); (A.S.J.)
| | - Mariusz R. Wieckowski
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland; (I.C.M.S.); (M.R.W.)
| | - José Teixeira
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, 3060-197 Cantanhede, Portugal; (R.A.); (C.V.); (A.C.); (R.F.S.); (J.T.)
- CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
| | - Paulo J. Oliveira
- CNC-Center for Neuroscience and Cell Biology, CIBB-Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, UC-Biotech, Biocant Park, 3060-197 Cantanhede, Portugal; (R.A.); (C.V.); (A.C.); (R.F.S.); (J.T.)
- Correspondence:
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30
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Demirel-Yalciner T, Sozen E, Ozaltin E, Sahin A, Ozer NK. alpha-Tocopherol supplementation reduces inflammation and apoptosis in high cholesterol mediated nonalcoholic steatohepatitis. Biofactors 2021; 47:403-413. [PMID: 34101924 DOI: 10.1002/biof.1700] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 10/06/2020] [Indexed: 12/19/2022]
Abstract
Inflammation and apoptosis signaling are crucial steps in the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH). Alpha-tocopherol, the most active form of vitamin E, is an important modulator of signaling mechanisms, but its involvement to cholesterol-induced NASH pathogenesis remains poorly defined. Herein we have reported a novel effect of α-tocopherol in the transition from hepatic steatosis to NASH. High cholesterol diet alone (without α-tocopherol) in rabbits elevated NASH development as indicated by increased inflammatory response, apoptotic activity and liver fibrosis. Such elevation results from induction of signaling mechanisms since the expressions of IL1β, phospho c-Jun/c-Jun ratio, JNK, caspase 9, CHOP and Bax were increased, and recruitment of macrophage, α-smooth muscle actin (α-SMA) and COL1A1 into the liver tissue were induced. Alpha-tocopherol supplementation inhibited inflammatory response, apoptosis and fibrosis development without affecting lipid accumulation in high cholesterol-induced NASH. Specifically, α-tocopherol lowered the inflammatory level as observed by reduced macrophage infiltration and JNK/c-Jun signaling. Lower inflammatory status co-occurred with the reduction of CHOP and Bax expressions as well as fibrosis-related COL1A1 and α-SMA levels. Taken together, α-tocopherol supplementation inhibits cholesterol-induced NASH development by lowering JNK/c-Jun/inflammation axis in addition to JNK/CHOP/apoptosis signaling, which might contribute to resistance against NAFLD/NASH transition.
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Affiliation(s)
- Tugce Demirel-Yalciner
- Department of Biochemistry, Faculty of Medicine, Genetic and Metabolic Diseases Research and Investigation Center (GEMHAM), Marmara University, Istanbul, Turkey
| | - Erdi Sozen
- Department of Biochemistry, Faculty of Medicine, Genetic and Metabolic Diseases Research and Investigation Center (GEMHAM), Marmara University, Istanbul, Turkey
| | - Esra Ozaltin
- Department of Biochemistry, Faculty of Medicine, Genetic and Metabolic Diseases Research and Investigation Center (GEMHAM), Marmara University, Istanbul, Turkey
| | - Ali Sahin
- Department of Biochemistry, Faculty of Medicine, Genetic and Metabolic Diseases Research and Investigation Center (GEMHAM), Marmara University, Istanbul, Turkey
| | - Nesrin Kartal Ozer
- Department of Biochemistry, Faculty of Medicine, Genetic and Metabolic Diseases Research and Investigation Center (GEMHAM), Marmara University, Istanbul, Turkey
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31
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Amodio G, Pagliara V, Moltedo O, Remondelli P. Structural and Functional Significance of the Endoplasmic Reticulum Unfolded Protein Response Transducers and Chaperones at the Mitochondria-ER Contacts: A Cancer Perspective. Front Cell Dev Biol 2021; 9:641194. [PMID: 33842465 PMCID: PMC8033034 DOI: 10.3389/fcell.2021.641194] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 02/22/2021] [Indexed: 01/15/2023] Open
Abstract
In the last decades, the endoplasmic reticulum (ER) has emerged as a key coordinator of cellular homeostasis, thanks to its physical interconnection to almost all intracellular organelles. In particular, an intense and mutual crosstalk between the ER and mitochondria occurs at the mitochondria–ER contacts (MERCs). MERCs ensure a fine-tuned regulation of fundamental cellular processes, involving cell fate decision, mitochondria dynamics, metabolism, and proteostasis, which plays a pivotal role in the tumorigenesis and therapeutic response of cancer cells. Intriguingly, recent studies have shown that different components of the unfolded protein response (UPR) machinery, including PERK, IRE1α, and ER chaperones, localize at MERCs. These proteins appear to exhibit multifaceted roles that expand beyond protein folding and UPR transduction and are often related to the control of calcium fluxes to the mitochondria, thus acquiring relevance to cell survival and death. In this review, we highlight the novel functions played by PERK, IRE1α, and ER chaperones at MERCs focusing on their impact on tumor development.
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Affiliation(s)
- Giuseppina Amodio
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana," University of Salerno, Baronissi, Italy
| | - Valentina Pagliara
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana," University of Salerno, Baronissi, Italy
| | - Ornella Moltedo
- Department of Pharmacy, University of Salerno, Fisciano, Italy
| | - Paolo Remondelli
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana," University of Salerno, Baronissi, Italy
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32
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Muthuraj PG, Sahoo PK, Kraus M, Bruett T, Annamalai AS, Pattnaik A, Pattnaik AK, Byrareddy SN, Natarajan SK. Zika virus infection induces endoplasmic reticulum stress and apoptosis in placental trophoblasts. Cell Death Discov 2021; 7:24. [PMID: 33500388 PMCID: PMC7838309 DOI: 10.1038/s41420-020-00379-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 11/13/2020] [Indexed: 01/30/2023] Open
Abstract
Zika virus (ZIKV) infection to a pregnant woman can be vertically transmitted to the fetus via the placenta leading to Congenital Zika syndrome. This is characterized by microcephaly, retinal defects, and intrauterine growth retardation. ZIKV induces placental trophoblast apoptosis leading to severe abnormalities in the growth and development of the fetus. However, the molecular mechanism behind ZIKV-induced apoptosis in placental trophoblasts remains unclear. We hypothesize that ZIKV infection induces endoplasmic reticulum (ER) stress in the trophoblasts, and sustained ER stress results in apoptosis. HTR-8 (HTR-8/SVneo), a human normal immortalized trophoblast cell and human choriocarcinoma-derived cell lines (JEG-3 and JAR) were infected with ZIKV. Biochemical and structural markers of apoptosis like caspase 3/7 activity and percent apoptotic nuclear morphological changes, respectively were assessed. ZIKV infection in placental trophoblasts showed an increase in the levels of CHOP mRNA and protein expression, which is an inducer of apoptosis. Next, we also observed increased levels of ER stress markers such as phosphorylated forms of inositol-requiring transmembrane kinase/endoribonuclease 1α (P-IRE1α), and its downstream target, the spliced form of XBP1 mRNA, phosphorylated eukaryotic initiation factor 2α (P-eIF2α), and activation of cJun N-terminal Kinase (JNK) and p38 mitogen activated protein kinase (MAPK) after 16-24 h of ZIKV infection in trophoblasts. Inhibition of JNK or pan-caspases using small molecule inhibitors significantly prevented ZIKV-induced apoptosis in trophoblasts. Further, JNK inhibition also reduced XBP1 mRNA splicing and viral E protein staining in ZIKV infected cells. In conclusion, the mechanism of ZIKV-induced placental trophoblast apoptosis involves the activation of ER stress and JNK activation, and the inhibition of JNK dramatically prevents ZIKV-induced trophoblast apoptosis.
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Affiliation(s)
- Philma Glora Muthuraj
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, 68583-0806, NE, USA
- Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE, USA
| | - Prakash K Sahoo
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, 68583-0806, NE, USA
- Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE, USA
| | - Madison Kraus
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, 68583-0806, NE, USA
- Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE, USA
| | - Taylor Bruett
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, 68583-0806, NE, USA
- Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE, USA
| | - Arun S Annamalai
- Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE, USA
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Omaha, NE, USA
| | - Aryamav Pattnaik
- Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE, USA
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Omaha, NE, USA
| | - Asit K Pattnaik
- Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE, USA
- School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Omaha, NE, USA
| | - Siddappa N Byrareddy
- Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE, USA
- Department of Pharmacology and Experimental Therapeutics, University of Nebraska Medical Center, Omaha, NE, USA
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sathish Kumar Natarajan
- Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, 68583-0806, NE, USA.
- Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE, USA.
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
- Child Health Research Institute, University of Nebraska Medical Center, Omaha, NE, USA.
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Tan X, Zhang Z, Liu P, Yao H, Shen L, Tong JS. Inhibition of EZH2 enhances the therapeutic effect of 5-FU via PUMA upregulation in colorectal cancer. Cell Death Dis 2020; 11:1061. [PMID: 33311453 PMCID: PMC7733595 DOI: 10.1038/s41419-020-03266-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 11/10/2020] [Accepted: 11/11/2020] [Indexed: 02/07/2023]
Abstract
Although the survival rate of patients with cancer have increased due to the use of current chemotherapeutic agents, adverse effects of cancer therapy remain a concern. The reversal of drug resistance, reduction in harmful side effects and accelerated increase in efficiency have often been addressed in the development of combination therapeutics. Tazemetostat (EPZ-6438), a histone methyltransferase EZH2 selective inhibitor, was approved by the FDA for the treatment of advanced epithelioid sarcoma. However, the effect of tazemetostat on colorectal cancer (CRC) and 5-FU sensitivity remains unclear. In this study, the enhancement of tazemetostat on 5-FU sensitivity was examined in CRC cells. Our findings demonstrated that tazemetostat combined with 5-FU exhibits synergistic antitumor function in vitro and in vivo in CRC cells. In addition, tazemetostat promotes PUMA induction through the ROS/ER stress/CHOP axis. PUMA depletion attenuates the antitumor effect of the combination therapy. Therefore, tazemetostat may be a novel treatment to improve the sensitivity of tumors to 5-FU in CRC therapy. In conclusion, the combination of 5-FU and tazemetostat shows high therapeutic possibility with reduced unfavorable effects.
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Affiliation(s)
- Xiao Tan
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, People's Republic of China.
| | - Zhongqiang Zhang
- Department of Liver Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, 410011, People's Republic of China
| | - Ping Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, People's Republic of China
| | - Hongliang Yao
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan Province, 410011, People's Republic of China
| | - Liangfang Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, People's Republic of China
| | - Jing-Shan Tong
- Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
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Zhang Y, Chatzistamou I, Kiaris H. Coordination of the unfolded protein response during hepatic steatosis identifies CHOP as a specific regulator of hepatocyte ballooning. Cell Stress Chaperones 2020; 25:969-978. [PMID: 32577989 PMCID: PMC7591657 DOI: 10.1007/s12192-020-01132-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 04/28/2020] [Accepted: 06/17/2020] [Indexed: 12/21/2022] Open
Abstract
The unfolded protein response (UPR) is an adaptive response that is implicated in multiple metabolic pathologies, including hepatic steatosis. In the present study, we analyzed publicly available RNAseq data to explore how the execution of the UPR is orchestrated in specimens that exhibit hepatocyte ballooning, a landmark feature of steatosis. By focusing on a panel of well-established UPR genes, we assessed how the UPR is coordinated with the whole transcriptome in specimens with or without hepatocyte ballooning. Our analyses showed that neither average levels nor correlation in expression between major UPR genes such as HSPA5 (BiP/GRP78), HSP90b1 (GRP94), or DDIT3 (CHOP) is altered in different groups. However, a panel of transcripts depending on the stringency of the analysis ranged from 16 to 372 lost its coordination with HSPA5, the major UPR chaperone, when hepatocyte ballooning occurred. In 13 genes, the majority of which is associated with metabolic processes, and the coordination with the HSPA5 was reversed from positive to negative in livers with ballooning hepatocytes. In order to examine if during ballooning, UPR genes abolish established and acquire novel functionalities, we performed gene ontology analyses. These studies showed that among the various UPR genes interrogated, only DDIT3 was not associated with conventional functions linked to endoplasmic reticulum stress during ballooning, while HSPA90b1 exhibited the highest function retention between the specimens with or without ballooning. Our results challenge conventional notions on the impact of specific genes in disease and suggest that besides abundance, the mode of coordination of UPR may be more important for disease development.
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Affiliation(s)
- Y Zhang
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, CLS 713, 715 Sumter St, Columbia, SC, USA
| | - I Chatzistamou
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, USA
| | - H Kiaris
- Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, CLS 713, 715 Sumter St, Columbia, SC, USA.
- Peromyscus Genetic Stock Center, University of South Carolina, CLS 713, 715 Sumter St, Columbia, SC, USA.
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Geng Y, Wu Z, Buist-Homan M, Blokzijl H, Moshage H. Hesperetin protects against palmitate-induced cellular toxicity via induction of GRP78 in hepatocytes. Toxicol Appl Pharmacol 2020; 404:115183. [PMID: 32763355 DOI: 10.1016/j.taap.2020.115183] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 07/29/2020] [Accepted: 08/01/2020] [Indexed: 12/19/2022]
Abstract
Lipotoxicity plays a critical role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Hesperetin, a flavonoid derivative, has anti-oxidant, anti-inflammatory and cytoprotective properties. In the present study, we aim to examine whether hesperetin protects against palmitate-induced lipotoxic cell death and to investigate the underlying mechanisms in hepatocytes. Primary rat hepatocytes and HepG2 cells were pretreated with hesperetin for 30 min and then exposed to palmitate (1.0 mmol/L in primary rat hepatocytes; 0.5 mmol/L in HepG2 cells) in the presence or absence of hesperetin. Necrotic cell death was measured via Sytox green nuclei staining and quantified by LDH release assay. Apoptotic cell death was determined by caspase 3/7 activity and the protein level of cleaved-PARP. The unfolded protein response (UPR) was assessed by measuring the expression of GRP78, sXBP1, ATF4 and CHOP. Results show that hesperetin (50 μmol/L and 100 μmol/L) protected against palmitate-induced cell death and inhibited palmitate-induced endoplasmic reticulum (ER) stress in both primary rat hepatocytes and HepG2 cells. Hesperetin (100 μmol/L) significantly activated sXBP1/GRP78 signaling, whereas a high concentration of hesperetin (200 μmol/L) activated p-eIF2α and caused hepatic cell death. Importantly, GRP78 knockdown via siRNA abolished the protective effects of hesperetin in HepG2 cells. In conclusion, hesperetin protected against palmitate-induced hepatic cell death via activation of the sXBP1/GRP78 signaling pathway, thus inhibiting palmitate-induced ER stress. Moreover, high concentrations of hesperetin induce ER stress and subsequently cause cell death in hepatocytes.
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Affiliation(s)
- Yana Geng
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
| | - Zongmei Wu
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
| | - Manon Buist-Homan
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
| | - Hans Blokzijl
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
| | - Han Moshage
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
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Attanasio S, Ferriero R, Gernoux G, De Cegli R, Carissimo A, Nusco E, Campione S, Teckman J, Mueller C, Piccolo P, Brunetti-Pierri N. CHOP and c-JUN up-regulate the mutant Z α 1-antitrypsin, exacerbating its aggregation and liver proteotoxicity. J Biol Chem 2020; 295:13213-13223. [PMID: 32723872 DOI: 10.1074/jbc.ra120.014307] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 07/23/2020] [Indexed: 12/16/2022] Open
Abstract
α1-Antitrypsin (AAT) encoded by the SERPINA1 gene is an acute-phase protein synthesized in the liver and secreted into the circulation. Its primary role is to protect lung tissue by inhibiting neutrophil elastase. The Z allele of SERPINA1 encodes a mutant AAT, named ATZ, that changes the protein structure and leads to its misfolding and polymerization, which cause endoplasmic reticulum (ER) stress and liver disease through a gain-of-function toxic mechanism. Hepatic retention of ATZ results in deficiency of one of the most important circulating proteinase inhibitors and predisposes to early-onset emphysema through a loss-of-function mechanism. The pathogenetic mechanisms underlying the liver disease are not completely understood. C/EBP-homologous protein (CHOP), a transcription factor induced by ER stress, was found among the most up-regulated genes in livers of PiZ mice that express ATZ and in human livers of patients homozygous for the Z allele. Compared with controls, juvenile PiZ/Chop -/- mice showed reduced hepatic ATZ and a transcriptional response indicative of decreased ER stress by RNA-Seq analysis. Livers of PiZ/Chop -/- mice also showed reduced SERPINA1 mRNA levels. By chromatin immunoprecipitations and luciferase reporter-based transfection assays, CHOP was found to up-regulate SERPINA1 cooperating with c-JUN, which was previously shown to up-regulate SERPINA1, thus aggravating hepatic accumulation of ATZ. Increased CHOP levels were detected in diseased livers of children homozygous for the Z allele. In summary, CHOP and c-JUN up-regulate SERPINA1 transcription and play an important role in hepatic disease by increasing the burden of proteotoxic ATZ, particularly in the pediatric population.
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Affiliation(s)
| | - Rosa Ferriero
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
| | - Gwladys Gernoux
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | | | - Annamaria Carissimo
- Institute for Applied Mathematics "Mauro Picone" National Research Council, Naples, Italy
| | - Edoardo Nusco
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
| | | | - Jeffrey Teckman
- St. Louis University School of Medicine, St. Louis, Missouri, USA
| | - Christian Mueller
- Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA; Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Pasquale Piccolo
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy; Department of Translational Medicine, Federico II University, Naples, Italy.
| | - Nicola Brunetti-Pierri
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy; Department of Translational Medicine, Federico II University, Naples, Italy.
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Borkham-Kamphorst E, Haas U, Van de Leur E, Trevanich A, Weiskirchen R. Chronic Carbon Tetrachloride Applications Induced Hepatocyte Apoptosis in Lipocalin 2 Null Mice Through Endoplasmic Reticulum Stress and Unfolded Protein Response. Int J Mol Sci 2020; 21:ijms21155230. [PMID: 32718038 PMCID: PMC7432394 DOI: 10.3390/ijms21155230] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/16/2020] [Accepted: 07/21/2020] [Indexed: 02/06/2023] Open
Abstract
The lack of Lipocalin (LCN2) provokes overwhelming endoplasmic reticulum (ER) stress responses in vitro and in acute toxic liver injury models, resulting in hepatocyte apoptosis. LCN2 is an acute phase protein produced in hepatocytes in response to acute liver injuries. In line with these findings we investigated ER stress responses of Lcn2−/− mice in chronic ER stress using a long-term repetitive carbon tetrachloride (CCl4) injection model. We found chronic CCl4 application to enhance ER stress and unfolded protein responses (UPR), including phosphorylation of eukaryotic initiation factor 2α (eIF2α), increased expression of binding immunoglobulin protein (BiP) and glucose-regulated protein 94 (GRP94). IRE1α/TRAF2/JNK signaling enhanced mitochondrial apoptotic pathways, and showed slightly higher in Lcn2−/− mice compared to the wild type counterparts, leading to increased hepatocyte apoptosis well evidenced by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Hepatocyte injuries were confirmed by significant high serum alanine transaminase (ALT) levels in CCl4-treated Lcn2−/− mice. Lcn2−/− mice furthermore developed mild hepatic steatosis, supporting our finding that ER stress promotes lipogenesis. In a previous report we demonstrated that the pharmacological agent tunicamycin (TM) induced ER stress through altered protein glycosylation and induced high amounts of C/EBP-homologous protein (CHOP), resulting in hepatocyte apoptosis. We compared TM-induced ER stress in wild type, Lcn2−/−, and Chop null (Chop−/−) primary hepatocytes and found Chop−/− hepatocytes to attenuate ER stress responses and resist ER stress-induced hepatocyte apoptosis through canonical eIF2α/GADD34 signaling, inhibiting protein synthesis. Unexpectedly, in later stages of TM incubation, Chop−/− hepatocytes resumed activation of IRE1α/JNK/c-Jun and p38/ATF2 signaling, leading to late hepatocyte apoptosis. This interesting observation indicates Chop−/− mice to be unable to absolutely prevent all types of liver injury, while LCN2 protects the hepatocytes by maintaining homeostasis under ER stress conditions.
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Affiliation(s)
- Erawan Borkham-Kamphorst
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University Hospital, D-52074 Aachen, Germany; (U.H.); (E.V.d.L.)
- Correspondence: (E.B.-K.); (R.W.); Tel.: +49-241-80-88684 (E.B.-K.); +49-241-80-88683 (R.W.)
| | - Ute Haas
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University Hospital, D-52074 Aachen, Germany; (U.H.); (E.V.d.L.)
| | - Eddy Van de Leur
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University Hospital, D-52074 Aachen, Germany; (U.H.); (E.V.d.L.)
| | - Anothai Trevanich
- Department of Statistics, Faculty of Science, Khon Kaen University, Khon Kaen 40002, Thailand;
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH Aachen University Hospital, D-52074 Aachen, Germany; (U.H.); (E.V.d.L.)
- Correspondence: (E.B.-K.); (R.W.); Tel.: +49-241-80-88684 (E.B.-K.); +49-241-80-88683 (R.W.)
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Processes exacerbating apoptosis in non-alcoholic steatohepatitis. Clin Sci (Lond) 2020; 133:2245-2264. [PMID: 31742325 DOI: 10.1042/cs20190068] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 10/28/2019] [Accepted: 11/04/2019] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a significant public health concern, owing to its high prevalence, progressive nature and lack of effective medical therapies. NAFLD is a complex and multifactorial disease involving the progressive and concerted action of factors that contribute to the development of liver inflammation and eventually fibrosis. Here, we summarize fundamental molecular mechanisms underlying the pathogenesis of non-alcoholic steatohepatitis (NASH), how they are interrelated and possible translation to clinical applications. We focus on processes triggering and exacerbating apoptotic signalling in the liver of NAFLD patients and their metabolic and pathological implications. Indeed, liver injury and inflammation are cardinal histopathological features of NASH, a duo in which derailment of apoptosis is of paramount importance. In turn, the liver houses a very high number of mitochondria, crucial metabolic unifiers of both extrinsic and intrinsic signals that converge in apoptosis activation. The role of lifestyle options is also dissected, highlighting the management of modifiable risk factors, such as obesity and harmful alcohol consumption, influencing apoptosis signalling in the liver and ultimately NAFLD progression. Integrating NAFLD-associated pathologic mechanisms in the cell death context could provide clues for a more profound understating of the disease and pave the way for novel rational therapies.
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Jagadish N, Devi S, Gupta N, Suri V, Suri A. Knockdown of A-kinase anchor protein 4 inhibits proliferation of triple-negative breast cancer cells in vitro and in vivo. Tumour Biol 2020; 42:1010428320914477. [PMID: 32342732 DOI: 10.1177/1010428320914477] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Triple-negative breast cancers are the most aggressive subtypes with poor prognosis due to lack of targeted cancer therapy. Recently, we reported an association of A-kinase anchor protein 4 expression with various clinico-pathological parameters of breast cancer patients. In this context, we examined the effect of knockdown of A-kinase anchor protein 4 on cell cycle, apoptosis, cellular proliferation, colony formation, migration, and invasion in triple-negative breast cancer cells. We also examined the synergistic cytotoxic effect of paclitaxel on A-kinase anchor protein 4 downregulated triple-negative breast cancer cells. Knockdown of A-kinase anchor protein 4 resulted in significant reduction in cellular growth and migratory abilities. Interestingly, we also observed enhanced cell death in A-kinase anchor protein 4 downregulated cells treated with paclitaxel. Knockdown of A-kinase anchor protein 4 in cell cycle resulted in G0/G1 phase arrest. Knockdown of A-kinase anchor protein 4 also led to increased reactive oxygen species generation as a result of upregulation of NOXA and CHOP. In addition, levels of cyclins, cyclin-dependent kinases, anti-apoptotic molecules, and mesenchymal markers were reduced in A-kinase anchor protein 4 downregulated cells. Moreover, downregulation of A-kinase anchor protein 4 also caused tumor growth reduction in in vivo studies. These data together suggest that A-kinase anchor protein 4 downregulation inhibits various malignant properties and enhances the cytotoxic effect of paclitaxel, and this combinatorial approach could be useful for triple-negative breast cancer treatment.
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Affiliation(s)
- Nirmala Jagadish
- Cancer Research Program, Cancer Microarray, Genes and Proteins Laboratory, National Institute of Immunology, New Delhi, India
| | - Sonika Devi
- Cancer Research Program, Cancer Microarray, Genes and Proteins Laboratory, National Institute of Immunology, New Delhi, India
| | - Namita Gupta
- Cancer Research Program, Cancer Microarray, Genes and Proteins Laboratory, National Institute of Immunology, New Delhi, India
| | - Vitusha Suri
- Mahatma Gandhi Medical College & Hospital, Jaipur, India
- SMS Medical College and Hospital, Jaipur, India
| | - Anil Suri
- Cancer Research Program, Cancer Microarray, Genes and Proteins Laboratory, National Institute of Immunology, New Delhi, India
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Electron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma. Nat Commun 2020; 11:1228. [PMID: 32144272 PMCID: PMC7060223 DOI: 10.1038/s41467-020-15051-z] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 02/18/2020] [Indexed: 11/24/2022] Open
Abstract
The BCL-2 antagonist venetoclax is highly effective in multiple myeloma (MM) patients exhibiting the 11;14 translocation, the mechanistic basis of which is unknown. In evaluating cellular energetics and metabolism of t(11;14) and non-t(11;14) MM, we determine that venetoclax-sensitive myeloma has reduced mitochondrial respiration. Consistent with this, low electron transport chain (ETC) Complex I and Complex II activities correlate with venetoclax sensitivity. Inhibition of Complex I, using IACS-010759, an orally bioavailable Complex I inhibitor in clinical trials, as well as succinate ubiquinone reductase (SQR) activity of Complex II, using thenoyltrifluoroacetone (TTFA) or introduction of SDHC R72C mutant, independently sensitize resistant MM to venetoclax. We demonstrate that ETC inhibition increases BCL-2 dependence and the ‘primed’ state via the ATF4-BIM/NOXA axis. Further, SQR activity correlates with venetoclax sensitivity in patient samples irrespective of t(11;14) status. Use of SQR activity in a functional-biomarker informed manner may better select for MM patients responsive to venetoclax therapy. Venetoclax monotherapy is effective in 40% of t(11:14) positive multiple myeloma (MM). Here, the authors show that electron transport chain complex I (CI) and complex II (CII) activity predict MM sensitivity to venetoclax, and inhibition of CI with IACS-010759 or CII with TTFA increase sensitivity.
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Parthasarathy G, Revelo X, Malhi H. Pathogenesis of Nonalcoholic Steatohepatitis: An Overview. Hepatol Commun 2020; 4:478-492. [PMID: 32258944 PMCID: PMC7109346 DOI: 10.1002/hep4.1479] [Citation(s) in RCA: 295] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 12/21/2019] [Indexed: 12/11/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a heterogeneous group of liver diseases characterized by the accumulation of fat in the liver. The heterogeneity of NAFLD is reflected in a clinical and histologic spectrum where some patients develop isolated steatosis of the liver, termed nonalcoholic fatty liver, whereas others develop hepatocyte injury, ballooning, inflammation, and consequent fibrosis, termed nonalcoholic steatohepatitis (NASH). Systemic insulin resistance is a major driver of hepatic steatosis in NAFLD. Lipotoxicity of accumulated lipids along with activation of the innate immune system are major drivers of NASH. Lipid‐induced sublethal and lethal stress culminates in the activation of inflammatory processes, such as the release of proinflammatory extracellular vesicles and cell death. Innate and adaptive immune mechanisms involving macrophages, dendritic cells, and lymphocytes are central drivers of inflammation that recognize damage‐ and pathogen‐associated molecular patterns and contribute to the progression of the inflammatory cascade. While the activation of the innate immune system and the recruitment of proinflammatory monocytes into the liver in NASH are well known, the exact signals that lead to this remain less well defined. Further, the contribution of other immune cell types, such as neutrophils and B cells, is an area of intense research. Many host factors, such as the microbiome and gut–liver axis, modify individual susceptibility to NASH. In this review, we discuss lipotoxicity, inflammation, and the contribution of interorgan crosstalk in NASH pathogenesis.
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Affiliation(s)
| | - Xavier Revelo
- Department of Integrative Biology and Physiology University of Minnesota Minneapolis MN
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology Mayo Clinic Rochester MN
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Li Z, Lv F, Dai C, Wang Q, Jiang C, Fang M, Xu Y. Activation of Galectin-3 (LGALS3) Transcription by Injurious Stimuli in the Liver Is Commonly Mediated by BRG1. Front Cell Dev Biol 2019; 7:310. [PMID: 31850346 PMCID: PMC6901944 DOI: 10.3389/fcell.2019.00310] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Accepted: 11/13/2019] [Indexed: 01/13/2023] Open
Abstract
Galectin-3 (encoded by LGALS3) is a glycan-binding protein that regulates a diverse range of pathophysiological processes contributing to the pathogenesis of human diseases. Previous studies have found that galectin-3 levels are up-regulated in the liver by a host of different injurious stimuli. The underlying epigenetic mechanism, however, is unclear. Here we report that conditional knockout of Brahma related gene (BRG1), a chromatin remodeling protein, in hepatocytes attenuated induction of galectin-3 expression in several different animal models of liver injury. Similarly, BRG1 depletion or pharmaceutical inhibition in cultured hepatocytes suppressed the induction of galectin-3 expression by treatment with LPS plus free fatty acid (palmitate). Further analysis revealed that BRG1 interacted with AP-1 to bind to the proximal galectin-3 promoter and activate transcription. Mechanistically, DNA demethylation surrounding the galectin-3 promoter appeared to be a rate-limiting step in BRG1-mediated activation of galectin-3 transcription. BRG1 recruited the DNA 5-methylcytosine dioxygenase TET1 to the galectin-3 to promote active DNA demethylation thereby activating galectin-3 transcription. Finally, TET1 silencing abrogated induction of galectin-3 expression by LPS plus palmitate in cultured hepatocytes. In conclusion, our data unveil a novel epigenetic pathway that contributes to injury-associated activation of galectin-3 transcription in hepatocytes.
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Affiliation(s)
- Zilong Li
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China
| | - Fangqiao Lv
- Department of Cell Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Congxin Dai
- Department of Neurosurgery, Peking Union Medical College Hospital, Beijing, China
| | - Qiong Wang
- Department of Surgical Oncology, the Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China
| | - Chao Jiang
- Department of Surgical Oncology, the Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, China
| | - Mingming Fang
- Department of Clinical Medicine, Laboratory Center for Basic Medical Sciences, Jiangsu Health Vocational College, Nanjing, China.,Institute of Biomedical Research, Liaocheng University, Liaocheng, China
| | - Yong Xu
- Key Laboratory of Targeted Intervention of Cardiovascular Disease and Collaborative Innovation Center for Cardiovascular Translational Medicine, Department of Pathophysiology, Nanjing Medical University, Nanjing, China.,Institute of Biomedical Research, Liaocheng University, Liaocheng, China
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Song MJ, Malhi H. The unfolded protein response and hepatic lipid metabolism in non alcoholic fatty liver disease. Pharmacol Ther 2019; 203:107401. [PMID: 31419516 PMCID: PMC6848795 DOI: 10.1016/j.pharmthera.2019.107401] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 08/08/2019] [Indexed: 12/19/2022]
Abstract
Nonalcoholic fatty liver disease is a major public health burden. Although many features of nonalcoholic fatty liver disease pathogenesis are known, the specific mechanisms and susceptibilities that determine an individual's risk of developing nonalcoholic steatohepatitis versus isolated steatosis are not well delineated. The predominant and defining histologic and imaging characteristic of nonalcoholic fatty liver disease is the accumulation of lipids. Dysregulation of lipid homeostasis in hepatocytes leads to transient generation or accumulation of toxic lipids that result in endoplasmic reticulum (ER) stress with inflammation, hepatocellular damage, and apoptosis. ER stress activates the unfolded protein response (UPR) which is classically viewed as an adaptive pathway to maintain protein folding homeostasis. Recent studies have uncovered the contribution of the UPR sensors in the regulation of hepatic steatosis and in the cellular response to lipotoxic stress. Interestingly, the UPR sensors can be directly activated by toxic lipids, independently of the accumulation of misfolded proteins, termed lipotoxic and proteotoxic stress, respectively. The dual function of the UPR sensors in protein and lipid homeostasis suggests that these two types of stress are interconnected likely due to the central role of the ER in protein folding and trafficking and lipid biosynthesis and trafficking, such that perturbations in either impact the function of the ER and activate the UPR sensors in an effort to restore homeostasis. The precise molecular similarities and differences between proteotoxic and lipotoxic ER stress are beginning to be understood. Herein, we provide an overview of the mechanisms involved in the activation and cross-talk between the UPR sensors, hepatic lipid metabolism, and lipotoxic stress, and discuss the possible therapeutic potential of targeting the UPR in nonalcoholic fatty liver disease.
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Affiliation(s)
- Myeong Jun Song
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States of America; Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States of America.
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Chen FY, Huang MY, Lin YM, Ho CH, Lin SY, Chen HY, Hung MC, Chen RH. BIK ubiquitination by the E3 ligase Cul5-ASB11 determines cell fate during cellular stress. J Cell Biol 2019; 218:3002-3018. [PMID: 31387940 PMCID: PMC6719446 DOI: 10.1083/jcb.201901156] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 06/04/2019] [Accepted: 07/01/2019] [Indexed: 12/16/2022] Open
Abstract
The BH3-only pro-apoptotic protein BIK is regulated by the ubiquitin-proteasome system. However, the mechanism of this regulation and its physiological functions remain elusive. Here, we identify Cul5-ASB11 as the E3 ligase targeting BIK for ubiquitination and degradation. ER stress leads to the activation of ASB11 by XBP1s during the adaptive phase of the unfolded protein response, which stimulates BIK ubiquitination, interaction with p97/VCP, and proteolysis. This mechanism of BIK degradation contributes to ER stress adaptation by promoting cell survival. Conversely, genotoxic agents down-regulate this IRE1α-XBP1s-ASB11 axis and stabilize BIK, which contributes in part to the apoptotic response to DNA damage. We show that blockade of this BIK degradation pathway by an IRE1α inhibitor can stabilize a BIK active mutant and increase its anti-tumor activity. Our study reveals that different cellular stresses regulate BIK ubiquitination by ASB11 in opposing directions, which determines whether or not cells survive, and that blocking BIK degradation has the potential to be used as an anti-cancer strategy.
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Affiliation(s)
- Fei-Yun Chen
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.,Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan
| | - Min-Yu Huang
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.,Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan
| | - Yu-Min Lin
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.,Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan
| | - Chi-Huan Ho
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.,Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan
| | - Shu-Yu Lin
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Hsin-Yi Chen
- Graduate Institute of Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Mien-Chie Hung
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.,Department of Biotechnology, Asia University, Taichung, Taiwan.,Center for Molecular Medicine and Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan
| | - Ruey-Hwa Chen
- Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan .,Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei, Taiwan
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45
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Korbecki J, Bajdak-Rusinek K. The effect of palmitic acid on inflammatory response in macrophages: an overview of molecular mechanisms. Inflamm Res 2019; 68:915-932. [PMID: 31363792 PMCID: PMC6813288 DOI: 10.1007/s00011-019-01273-5] [Citation(s) in RCA: 299] [Impact Index Per Article: 49.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 07/22/2019] [Accepted: 07/23/2019] [Indexed: 02/06/2023] Open
Abstract
Palmitic acid is a saturated fatty acid whose blood concentration is elevated in obese patients. This causes inflammatory responses, where toll-like receptors (TLR), TLR2 and TLR4, play an important role. Nevertheless, palmitic acid is not only a TLR agonist. In the cell, this fatty acid is converted into phospholipids, diacylglycerol and ceramides. They trigger the activation of various signaling pathways that are common for LPS-mediated TLR4 activation. In particular, metabolic products of palmitic acid affect the activation of various PKCs, ER stress and cause an increase in ROS generation. Thanks to this, palmitic acid also strengthens the TLR4-induced signaling. In this review, we discuss the mechanisms of inflammatory response induced by palmitic acid. In particular, we focus on describing its effect on ER stress and IRE1α, and the mechanisms of NF-κB activation. We also present the mechanisms of inflammasome NLRP3 activation and the effect of palmitic acid on enhanced inflammatory response by increasing the expression of FABP4/aP2. Finally, we focus on the consequences of inflammatory responses, in particular, the effect of TNF-α, IL-1β and IL-6 on insulin resistance. Due to the high importance of macrophages and the production of proinflammatory cytokines by them, this work mainly focuses on these cells.
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Affiliation(s)
- Jan Korbecki
- Department of Molecular Biology, School of Medicine in Katowice, Medical University of Silesia, Medyków 18 St., 40-752, Katowice, Poland.
| | - Karolina Bajdak-Rusinek
- Department of Medical Genetics, School of Medicine in Katowice, Medical University of Silesia, Medyków 18 St., 40-752, Katowice, Poland
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Abstract
Endoplasmic reticulum (ER) stress is a major contributor to liver disease and hepatic fibrosis, but the role it plays varies depending on the cause and progression of the disease. Furthermore, ER stress plays a distinct role in hepatocytes versus hepatic stellate cells (HSCs), which adds to the complexity of understanding ER stress and its downstream signaling through the unfolded protein response (UPR) in liver disease. Here, the authors focus on the current literature of ER stress in nonalcoholic and alcoholic fatty liver diseases, how ER stress impacts hepatocyte injury, and the role of ER stress in HSC activation and hepatic fibrosis. This review provides insight into the complex signaling and regulation of the UPR, parallels and distinctions between different liver diseases, and how ER stress may be targeted as an antisteatotic or antifibrotic therapy to limit the progression of liver disease.
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Affiliation(s)
- Jessica L. Maiers
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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47
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Gazzano E, Buondonno I, Marengo A, Rolando B, Chegaev K, Kopecka J, Saponara S, Sorge M, Hattinger CM, Gasco A, Fruttero R, Brancaccio M, Serra M, Stella B, Fattal E, Arpicco S, Riganti C. Hyaluronated liposomes containing H2S-releasing doxorubicin are effective against P-glycoprotein-positive/doxorubicin-resistant osteosarcoma cells and xenografts. Cancer Lett 2019; 456:29-39. [PMID: 31047947 DOI: 10.1016/j.canlet.2019.04.029] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Revised: 04/18/2019] [Accepted: 04/25/2019] [Indexed: 12/16/2022]
Abstract
Doxorubicin (dox) is one of the first-line drug in osteosarcoma treatment but its effectiveness is limited by the efflux pump P-glycoprotein (Pgp) and by the onset of cardiotoxicity. We previously demonstrated that synthetic doxs conjugated with a H2S-releasing moiety (Sdox) were less cardiotoxic and more effective than dox against Pgp-overexpressing osteosarcoma cells. In order to increase the active delivery to tumor cells, we produced hyaluronic acid (HA)-conjugated liposomes containing Sdox (HA-Lsdox), exploiting the abundance of the HA receptor CD44 in osteosarcoma. HA-Lsdox showed favorable drug-release profile and higher toxicity in vitro and in vivo than dox or the FDA-approved liposomal dox Caelyx® against Pgp-overexpressing osteosarcoma, displaying the same cardiotoxicity profile of Caelyx®. Differently from dox, HA-Lsdox delivered the drug within the endoplasmic reticulum (ER), inducing protein sulfhydration and ubiquitination, and activating a ER stress pro-apoptotic response mediated by CHOP. HA-Lsdox also sulfhydrated the nascent Pgp in the ER, reducing its activity. We propose HA-Lsdox as an innovative tool noteworthy to be tested in Pgp-overexpressing patients, who are frequently less responsive to standard treatments in which dox is one of the most important drugs.
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Affiliation(s)
- Elena Gazzano
- Department of Oncology, University of Torino, Torino, Italy
| | | | - Alessandro Marengo
- Department of Drug Science and Technology, University of Torino, Torino, Italy
| | - Barbara Rolando
- Department of Drug Science and Technology, University of Torino, Torino, Italy
| | - Konstantin Chegaev
- Department of Drug Science and Technology, University of Torino, Torino, Italy
| | - Joanna Kopecka
- Department of Oncology, University of Torino, Torino, Italy
| | - Simona Saponara
- Department of Life Sciences, University of Siena, Siena, Italy
| | - Matteo Sorge
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Claudia Maria Hattinger
- IRCCS Istituto Ortopedico Rizzoli, Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit, Bologna, Italy
| | - Alberto Gasco
- Department of Drug Science and Technology, University of Torino, Torino, Italy
| | - Roberta Fruttero
- Department of Drug Science and Technology, University of Torino, Torino, Italy
| | - Mara Brancaccio
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Massimo Serra
- IRCCS Istituto Ortopedico Rizzoli, Laboratory of Experimental Oncology, Pharmacogenomics and Pharmacogenetics Research Unit, Bologna, Italy
| | - Barbara Stella
- Department of Drug Science and Technology, University of Torino, Torino, Italy
| | - Elias Fattal
- Institut Galien Paris-Sud, CNRS, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France
| | - Silvia Arpicco
- Department of Drug Science and Technology, University of Torino, Torino, Italy.
| | - Chiara Riganti
- Department of Oncology, University of Torino, Torino, Italy.
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Serrano-Del Valle A, Anel A, Naval J, Marzo I. Immunogenic Cell Death and Immunotherapy of Multiple Myeloma. Front Cell Dev Biol 2019; 7:50. [PMID: 31041312 PMCID: PMC6476910 DOI: 10.3389/fcell.2019.00050] [Citation(s) in RCA: 141] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 03/19/2019] [Indexed: 12/24/2022] Open
Abstract
Over the past decades, immunotherapy has demonstrated a prominent clinical efficacy in a wide variety of human tumors. For many years, apoptosis has been considered a non-immunogenic or tolerogenic process whereas necrosis or necroptosis has long been acknowledged to play a key role in inflammation and immune-related processes. However, the new concept of “immunogenic cell death” (ICD) has challenged this traditional view and has granted apoptosis with immunogenic abilities. This paradigm shift offers clear implications in designing novel anti-cancer therapeutic approaches. To date, several screening studies have been carried out to discover bona fide ICD inducers and reveal the inherent capacity of a wide variety of drugs to induce cell death-associated exposure of danger signals and to bring about in vivo anti-cancer immune responses. Recent shreds of evidence place ER stress at the core of all the scenarios where ICD occur. Furthermore, ER stress and the unfolded protein response (UPR) have emerged as important targets in different human cancers. Notably, in multiple myeloma (MM), a lethal plasma cell disorder, the elevated production of immunoglobulins leaves these cells heavily reliant on the survival arm of the UPR. For that reason, drugs that disrupt ER homeostasis and engage ER stress-associated cell death, such as proteasome inhibitors, which are currently used for the treatment of MM, as well as novel ER stressors are intended to be promising therapeutic agents in MM. This not only holds true for their capacity to induce cell death, but also to their potential ability to activate the immunogenic arm of the ER stress response, with the ensuing exposure of danger signals. We provide here an overview of the up-to-date knowledge regarding the cell death mechanisms involved in situations of ER stress with a special focus on the connections with the drug-induced ER stress pathways that evoke ICD. We will also discuss how this could assist in optimizing and developing better immunotherapeutic approaches, especially in MM treatment.
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Affiliation(s)
| | - Alberto Anel
- Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, Zaragoza, Spain
| | - Javier Naval
- Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, Zaragoza, Spain
| | - Isabel Marzo
- Department of Biochemistry and Molecular and Cell Biology, University of Zaragoza, Zaragoza, Spain
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49
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Shakib N, Khadem Ansari MH, Karimi P, Rasmi Y. Neuroprotective mechanism of low-dose sodium nitrite in oxygen-glucose deprivation model of cerebral ischemic stroke in PC12 cells. EXCLI JOURNAL 2019; 18:229-242. [PMID: 31217786 PMCID: PMC6558507 DOI: 10.17179/excli2018-1947] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 03/26/2019] [Indexed: 01/29/2023]
Abstract
The purpose of this study was to clarify the mechanisms of the protective effects of low-dose sodium nitrite (SN) on oxygen and glucose deprivation (OGD)-induced endoplasmic reticulum (ER) stress in PC12 cells. The PC12 cells were exposed to 4 h of OGD and treated with 100 μmol SN. The expression and activity of ER stress markers, including PKR-like endoplasmic reticulum kinase (PERK), transcription factor 6 (ATF6), CCAAT/enhancer binding protein homologous protein (CHOP), as well as caspase-12 and -3, were detected by immunoblotting assay. Fluorescence staining was used to detect the levels of reactive oxygen species (ROS) and Ca2+ release from the ER. Cell viability was also evaluated by MTT assay. It was found that SN significantly inhibited ROS production and Ca2+ release from the ER in OGD-injured PC12 cells. Moreover, ER stress marker expression and cleaved fragments of caspase-3 and -12 in OGD-injured PC12 cells were decreased after SN treatment. These findings were accompanied by a significant increase in cell viability. It seems that SN exerts a neuroprotective effect at least partially through reduction of ROS-mediated ER stress caused by OGD insult.
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Affiliation(s)
- Nader Shakib
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | | | - Pouran Karimi
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Yousef Rasmi
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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50
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Isobe T, Tange S, Tasaki H, Kanamori K, Kato A, Nakanishi A. Upregulation of CHOP participates in caspase activation and virus release in human astrovirus-infected cells. J Gen Virol 2019; 100:778-792. [PMID: 30912739 DOI: 10.1099/jgv.0.001250] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Human astroviruses (HAstVs), non-enveloped RNA viruses with positive-sense RNA genomes, are an important cause of acute gastroenteritis in young children, although the processes that produce infectious virions are not clearly defined. To track the viral replication complex (RC) upon HAstV1 infection, the subcellular distribution of double-stranded (ds) RNA and of ORF1b, a viral RNA polymerase, was examined by immunocytochemistry. Foci that were positive for dsRNA and for ORF1b were co-localized, and both foci were also co-localized with resident proteins of the endoplasmic reticulum (ER). Focusing on the association between the HAstV RC and ER, we examined the expression of unfolded protein response (UPR) markers and found that targets of eukaryotic translation initiation factor 2α (eIF2α)-activating transcription factor 4 (ATF4), including CCAAT/enhancer-binding protein homologous protein (CHOP), a proapoptotic transcription factor, were upregulated at the late phase in HAstV-infected cells. Consistently, eIF2α was phosphorylated at the late phase of HAstV infection. The formation of foci resembling stress granules, another known downstream response to eIF2α phosphorylation, was also observed at the same period. Phosphorylation of eIF2α was attenuated in protein kinase R (PKR)-knockdown cells, suggesting that, unlike the canonical ER stress response, PKR was involved in eIF2α phosphorylation in response to HAstV infection. Studies have indicated that immature HAstV capsid protein is processed by caspases, and caspase cleavage is integral to particle release. Inhibition of CHOP upregulation reduced caspase activation and the release of HAstV RNA from cells during HAstV infection. Our results suggest that the eIF2α-ATF4-CHOP pathway participates in HAstV propagation.
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Affiliation(s)
- Tomoyasu Isobe
- 1Section of Gene Therapy, Department of Aging Intervention, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8522, Japan
| | - Shoichiro Tange
- 2Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, 060-8556, Japan
| | | | - Kumiko Kanamori
- 1Section of Gene Therapy, Department of Aging Intervention, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8522, Japan
| | - Akiko Kato
- 4Laboratory of Radiation Safety, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8522, Japan
| | - Akira Nakanishi
- 1Section of Gene Therapy, Department of Aging Intervention, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8522, Japan.,4Laboratory of Radiation Safety, National Center for Geriatrics and Gerontology, Obu, Aichi, 474-8522, Japan
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