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Qin D, Huang P, Chen J, Wu C, Liang Y. The therapeutic potential of different mesenchymal stem cells and their derived exosomes in metabolic dysfunction-associated steatotic liver disease. Front Endocrinol (Lausanne) 2025; 16:1558194. [PMID: 40248144 PMCID: PMC12003127 DOI: 10.3389/fendo.2025.1558194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 03/14/2025] [Indexed: 04/19/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease is a metabolic disease with an increasing incidence. Its pathogenesis involves the interaction of multiple factors. There is currently no specific treatment, so early prevention and treatment are crucial. Mesenchymal stem cells are a type of cell with the ability to self-renew and differentiate in multiple directions. They have a wide range of sources, including umbilical cords, bone marrow, and fat, and have various biological functions such as anti-inflammation, immune regulation, anti-oxidation, and inhibition of fibrosis. They have shown significant potential in the treatment of non-alcoholic fatty liver disease. In recent years, mesenchymal stem cells derived exosomes have been shown to be rich in bioactive substances, and to be involved in intercellular communication, regulating metabolism, reducing inflammatory responses, improving lipid metabolism, inhibiting fibrosis, and other processes that contribute to the treatment of metabolic dysfunction-associated steatotic liver disease. Mesenchymal stem cells and mesenchymal stem cell-derived exosomes play an important role in the pathogenesis and treatment of metabolic dysfunction-associated steatotic liver disease and provide new potential and direction for the treatment of Metabolic dysfunction-associated steatotic liver disease. This article reviews the role and effects of mesenchymal stem cells and mesenchymal stem cell-derived exosomes from different sources in Metabolic dysfunction-associated steatotic liver disease and discusses their prospects as potential therapeutic strategies.
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Affiliation(s)
- Dan Qin
- Department of Endocrinology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Pingping Huang
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jialing Chen
- Department of Endocrinology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Changjun Wu
- Department of Endocrinology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yuzhen Liang
- Department of Endocrinology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
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Xu Q, Wang X, Hu J, Wang Y, Lu S, Xiong J, Li H, Xiong N, Huang Y, Wang Y, Wang Z. Overexpression of hnRNPK and inhibition of cytoplasmic translocation ameliorate lipid disorder in doxorubicin-induced cardiomyopathy via PINK1/Parkin-mediated mitophagy. Free Radic Biol Med 2025; 231:94-108. [PMID: 39984063 DOI: 10.1016/j.freeradbiomed.2025.02.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 02/08/2025] [Accepted: 02/14/2025] [Indexed: 02/23/2025]
Abstract
Lipid metabolism has been identified as a potential target for the treatment of doxorubicin-induced cardiomyopathy (DIC). Mitochondria, as a central regulator of energy production and utilization, plays a crucial role in this process, and enhancing mitophagy holds promise in mitigating myocardial damage in DIC. However, the relationship between mitophagy and lipid metabolism remains unclear, and the key molecules mediating this connection remain to be elucidated. Among these candidates, heterogeneous nuclear ribonucleoprotein K (hnRNPK) emerges as a potential regulator of mitophagy and metabolism. However, its specific role in DIC remains unclear. In this study, we established chronic DIC models both in vivo and in vitro to assess the relationship between hnRNPK levels, mitophagy, and lipid metabolism, as well as to evaluate the impact of hnRNPK on cardiac function. Our findings revealed that hnRNPK expression is significantly reduced in the hearts of doxorubicin (DOX)-treated mice. Notably, hnRNPK overexpression improves cardiac function and effectively reduces lipid accumulation by enhancing mitophagy. Mechanistically, hnRNPK expression was found to be downregulated in DIC, accompanied by its translocation from the nucleus to the cytoplasm, thereby reducing the transcriptional regulation of PINK1. Overexpression of hnRNPK and inhibition of its cytoplasmic translocation alleviates DOX-induced lipid accumulation by regulating the PINK1/Parkin pathway. These findings underscore a previously unrecognized role of hnRNPK in inhibiting lipid accumulation to prevent DIC.
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Affiliation(s)
- Qian Xu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Xuehua Wang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Jing Hu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Ya Wang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Shuai Lu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Jingjie Xiong
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Han Li
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Ni Xiong
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - YanLing Huang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China
| | - Yan Wang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
| | - Zhaohui Wang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China; Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
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Shao C, Lan W, Ding Y, Ye L, Huang J, Liang X, He Y, Zhang J. JTCD attenuates HF by inhibiting activation of HSCs through PPARα-TFEB axis-mediated lipophagy. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 139:156501. [PMID: 39978277 DOI: 10.1016/j.phymed.2025.156501] [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: 10/10/2024] [Revised: 12/28/2024] [Accepted: 02/11/2025] [Indexed: 02/22/2025]
Abstract
BACKGROUND Hepatic fibrosis (HF) is an intermediate stage in the progression of chronic liver disease to cirrhosis and has been shown to be a reversible pathological process. Known evidence suggests that activation of hepatic stellate cells (HSCs) and degradation of their lipid droplets (LDs) play an indispensable role in the process of HF. Jiawei Taohe Chengqi Decoction (JTCD) can inhibit the activation of HSCs in the process of HF, but the exact mechanism remains to be elucidated. PURPOSE The aim of this study is to determine whether JTCD inhibits lipophagy and to explore the possible mechanisms of its HF effect in HSCs by regulating the PPARα/TFEB axis. METHODS Network pharmacology and molecular docking were firstly applied to predict the potential mechanism of JTCD for the treatment of HF. In vivo, a mouse model of HF was constructed using carbon tetrachloride (CCl4) solution, and the efficacy of JTCD was assessed by staining of pathological sections, oil red O staining, immunofluorescence (IF), immunohistochemistry (IHC) staining, Western blotting and qRT-PCR. The intervention of JTCD was verified in vitro by induction of activated LX-2 cells with TGF-β solution and intervention using agonists and antagonists of PPARα. Finally, transient transfection of cells using TFEB siRNA was performed for validation studies. RESULTS JTCD effectively alleviated CCl4-induced HF in mice and reduced the levels of HF markers α-smooth muscle actin (α-SMA) and collagen I (COL1A1), and inhibited PPARα expression and lipophagy process. In vitro, JTCD delayed the degradation of LDs and reduced lipophagy in LX-2 cells, suggesting a mechanism involving PPARα/TFEB axis signaling regulation.
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Affiliation(s)
- Chang Shao
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Wenfang Lan
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Ying Ding
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Linmao Ye
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Jiaxin Huang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Xiaofan Liang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Yi He
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Junjie Zhang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
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Wang Y, Diao P, Aomura D, Nimura T, Harada M, Jia F, Nakajima T, Tanaka N, Kamijo Y. Dietary Polyunsaturated Fatty Acid Deficiency Impairs Renal Lipid Metabolism and Adaptive Response to Proteinuria in Murine Renal Tubules. Nutrients 2025; 17:961. [PMID: 40289946 PMCID: PMC11944481 DOI: 10.3390/nu17060961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 02/27/2025] [Accepted: 03/05/2025] [Indexed: 04/30/2025] Open
Abstract
Background/Objectives: Kidneys are fatty acid (FA)-consuming organs that use adenosine triphosphate (ATP) for tubular functions, including endocytosis for protein reabsorption to prevent urinary protein loss. Peroxisome proliferator-activated receptor α (PPARα) is a master regulator of FA metabolism and energy production, with high renal expression. Although polyunsaturated fatty acids (PUFAs) are essential nutrients that are natural PPARα ligands, their role in tubular protein reabsorption remains unclear. As clinical PUFA deficiency occurs in humans under various conditions, we used a mouse model that mimics these conditions. Methods: We administered a 2-week intraperitoneal protein-overload (PO) treatment to mice that had been continuously fed a PUFA-deficient diet. We compared the phenotypic changes with those in mice fed a standard diet and those in mice fed a PUFA-deficient diet with PUFA supplementation. Results: In the absence of PO, the PUFA-deficient diet induced increased lysosomal autophagy activation; however, other phenotypic differences were not detected among the diet groups. In the PO experimental condition, the PUFA-deficient diet increased daily urinary protein excretion and tubular lysosomes; suppressed adaptive endocytosis activation, which was probably enhanced by continuous autophagy activation; and worsened FA metabolism and PPARα-mediated responses to PO, which disrupted renal energy homeostasis. However, these changes were attenuated by PUFA supplementation at the physiological intake level. Conclusions: PUFAs are essential nutrients for the tubular adaptive reabsorption response against urinary protein loss. Therefore, active PUFA intake may be important for patients with kidney disease-associated proteinuria, especially those with various PUFA deficiency-inducing conditions.
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Affiliation(s)
- Yaping Wang
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; (Y.W.); (F.J.); (T.N.); (N.T.)
- Basic Nursing, Hebei Medical University, Shijiazhuang 050017, China
| | - Pan Diao
- Department of Clinical Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang 050017, China;
- Postdoctoral Mobile Station of Clinical Medicine, Hebei Medical University, Shijiazhuang 050017, China
| | - Daiki Aomura
- Department of Nephrology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; (D.A.); (T.N.); (M.H.)
| | - Takayuki Nimura
- Department of Nephrology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; (D.A.); (T.N.); (M.H.)
| | - Makoto Harada
- Department of Nephrology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; (D.A.); (T.N.); (M.H.)
| | - Fangping Jia
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; (Y.W.); (F.J.); (T.N.); (N.T.)
- Department of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Takero Nakajima
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; (Y.W.); (F.J.); (T.N.); (N.T.)
- Center for Medical Education and Clinical Training, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
| | - Naoki Tanaka
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; (Y.W.); (F.J.); (T.N.); (N.T.)
- Department of Global Medical Research Promotion, Shinshu University Graduate School of Medicine, Matsumoto 390-8621, Japan
- International Relations Office, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
- Research Center for Social Systems, Shinshu University, Matsumoto 390-8621, Japan
| | - Yuji Kamijo
- Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; (Y.W.); (F.J.); (T.N.); (N.T.)
- Department of Nephrology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; (D.A.); (T.N.); (M.H.)
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Zubairu IK, Rakariyatham K, Bai-Ngew S, Leksawasdi N, Regenstein JM, Lao F, Hong H, Shin WS, Alzahrani KJ, Phimolsiripol Y. Nutritional and Therapeutic Potential of Longan Fruit By-products for Liver Diseases: Pathway to Functional Foods. Curr Nutr Rep 2025; 14:28. [PMID: 39907839 DOI: 10.1007/s13668-025-00617-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/22/2025] [Indexed: 02/06/2025]
Abstract
PURPOSE OF REVIEW The massive processing of longan fruit consequently generates a significant quantity of by-products that are a nuisance to the environment. This review aims to tap these by-products for sustainable applications in treating hepatic diseases. RECENT FINDINGS Ethnobotanical investigations show that longan fruit has been utilized in liver functioning for over two millennia and is supported by contemporary scientific findings. Recent studies highlighted that these by-products contain bioactive compounds that decrease oxidative stress and inflammation, key drivers of liver diseases, including liver fibrosis, hepatitis, and non-alcoholic fatty liver disease (NAFLD). These bioactive compounds modulate lipid metabolism, detoxification pathways, and oxidative stress-regulating metabolic pathways of hepatoprotection. In addition, using longan by-products provides a relatively more affordable nutraceutical substitute for synthetic pharmaceuticals. This literature revealed that polyphenolic compounds such as corilagin gallic acid, ellagic acid, and various flavonoids in longan by-products exhibit antioxidant, anti-inflammatory, and immunomodulatory activities that benefit liver health through different pathways including unexplored mechanisms. However, this review recommends exploring the potential functional application of these by-products in food. It emphasizes the need for clinical validation of longan by-product therapies for liver diseases.
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Affiliation(s)
- Idris Kaida Zubairu
- Faculty of Agro-Industry, Chiang Mai University, Chiang Mai, 50100, Thailand
| | | | - Shitapan Bai-Ngew
- Faculty of Agro-Industry, Chiang Mai University, Chiang Mai, 50100, Thailand
| | - Noppol Leksawasdi
- Faculty of Agro-Industry, Chiang Mai University, Chiang Mai, 50100, Thailand
| | - Joe M Regenstein
- Department of Food Science, Cornell University, Ithaca, NY, 14853-7201, USA
| | - Fei Lao
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Hui Hong
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
| | - Weon-Sun Shin
- College of Human Ecology, Hanyang University, Seoul, Republic of Korea
| | - Khalid J Alzahrani
- Department of Clinical Laboratories Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia
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Tian L, Su F, Zhu X, Zou X. The Effect of Maternal Obesity on Placental Autophagy in Lean Breed Sows. Vet Sci 2025; 12:97. [PMID: 40005857 PMCID: PMC11861729 DOI: 10.3390/vetsci12020097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 01/17/2025] [Accepted: 01/24/2025] [Indexed: 02/27/2025] Open
Abstract
This study aimed to evaluate the influence of back-fat thickness (BF), at mating of sows, on autophagy in placenta and the potential mechanism. The sows were divided into two groups according to their BF at mating: BFI (15-20 mm, n = 14) and BFII (21-27 mm, n = 14) as the maternal obesity group. The placental samples used for investigating autophagic function and fatty acid profiles were obtained by vaginal delivery. Our results demonstrated that autophagy defects were observed in placenta from BFII sows along with altered circulating and placental fatty acid profiles. Indicative of impaired autophagy, reduced autophagic vesicles as well as LC3-positive puncta were linked to decreased mRNA or protein expression of autophagy-related genes, including ATG5, ATG7, Beclin1, ATG12, LC3, LAMP1 and LAMP2 in the placenta of BFII sows (p < 0.05). Meanwhile, we found reduced conversion of LC3-I to LC3-II and up-regulated protein content of p62 in the placenta from BFII group (p < 0.05). Furthermore, excessive back-fat was also associated with increased activation of AKT/mTOR signaling and decreased mRNA content of transcription factors regulating the autophagic pathway, including PPARα and PGC1α, but increased mRNA expression of NcoR1 in placenta. Together, these findings indicate that maternal obesity incites autophagy injury in pig term placenta, which may contribute to augmented placental lipid accumulation and therefore impaired placental function.
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Affiliation(s)
- Liang Tian
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
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Tripathi M, Gauthier K, Sandireddy R, Zhou J, Guptta P, Sakthivel S, Teo WW, Naing YT, Arul K, Tikno K, Park SH, Wu Y, Wang L, Bay BH, Sun L, Giguere V, Chow PKH, Ghosh S, McDonnell DP, Yen PM, Singh BK. Esrra regulates Rplp1-mediated translation of lysosome proteins suppressed in metabolic dysfunction-associated steatohepatitis and reversed by alternate day fasting. Mol Metab 2024; 87:101997. [PMID: 39032642 PMCID: PMC11327444 DOI: 10.1016/j.molmet.2024.101997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 07/03/2024] [Accepted: 07/17/2024] [Indexed: 07/23/2024] Open
Abstract
OBJECTIVE Currently, little is known about the mechanism(s) regulating global and specific protein translation during metabolic dysfunction-associated steatohepatitis (MASH; previously known as non-alcoholic steatohepatitis, NASH). METHODS Unbiased label-free quantitative proteome, puromycin-labelling and polysome profiling were used to understand protein translation activity in vitro and in vivo. RESULTS We observed a global decrease in protein translation during lipotoxicity in human primary hepatocytes, mouse hepatic AML12 cells, and livers from a dietary mouse model of MASH. Interestingly, proteomic analysis showed that Rplp1, which regulates ribosome and translation pathways, was one of the most downregulated proteins. Moreover, decreased Esrra expression and binding to the Rplp1 promoter, diminished Rplp1 gene expression during lipotoxicity. This, in turn, reduced global protein translation and Esrra/Rplp1-dependent translation of lysosome (Lamp2, Ctsd) and autophagy (sqstm1, Map1lc3b) proteins. Of note, Esrra did not increase its binding to these gene promoters or their gene transcription, confirming its regulation of their translation during lipotoxicity. Notably, hepatic Esrra-Rplp1-dependent translation of lysosomal and autophagy proteins also was impaired in MASH patients and liver-specific Esrra knockout mice. Remarkably, alternate day fasting induced Esrra-Rplp1-dependent expression of lysosomal proteins, restored autophagy, and reduced lipotoxicity, inflammation, and fibrosis in hepatic cell culture and in vivo models of MASH. CONCLUSIONS Esrra regulation of Rplp1-mediated translation of lysosome/autolysosome proteins was downregulated during MASH. Alternate day fasting activated this novel pathway and improved MASH, suggesting that Esrra and Rplp1 may serve as therapeutic targets for MASH. Our findings also provided the first example of a nuclear hormone receptor, Esrra, to not only regulate transcription but also protein translation, via induction of Rplp1.
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Affiliation(s)
- Madhulika Tripathi
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore
| | - Karine Gauthier
- Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Université Lyon 1, CNRS, Ecole Normale Supérieure de Lyon, 46 Allée d'Italie 69364 Lyon Cedex 07, France
| | - Reddemma Sandireddy
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore
| | - Jin Zhou
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore
| | - Priyanka Guptta
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore
| | - Suganya Sakthivel
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore
| | - Wei Wen Teo
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore
| | - Yadanar Than Naing
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore
| | - Kabilesh Arul
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore
| | - Keziah Tikno
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore
| | - Sung-Hee Park
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, C238A Levine Science Research Center, Durham, NC 27710, USA
| | - Yajun Wu
- Department of Anatomy, Yong Loo Lin School of Medicine, NUS 117594, Singapore
| | - Lijin Wang
- Centre for Computational Biology, Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore; Pennington Biomedical Research Center, Laboratory of Bioinformatics and Computational Biology, Baton Rouge, LA 70808, USA
| | - Boon-Huat Bay
- Department of Anatomy, Yong Loo Lin School of Medicine, NUS 117594, Singapore
| | - Lei Sun
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore
| | - Vincent Giguere
- Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montreal, Québec H3A 1A3, Canada
| | - Pierce K H Chow
- Dept of Surgery, Singapore General Hospital and Dept. of Surgical Oncology, National Cancer Centre 169608, Singapore
| | - Sujoy Ghosh
- Centre for Computational Biology, Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore; Pennington Biomedical Research Center, Laboratory of Bioinformatics and Computational Biology, Baton Rouge, LA 70808, USA
| | - Donald P McDonnell
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, C238A Levine Science Research Center, Durham, NC 27710, USA
| | - Paul M Yen
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore; Duke Molecular Physiology Institute and Dept. of Medicine, Duke University School of Medicine, Durham, NC 27710, USA
| | - Brijesh K Singh
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore (NUS) Medical School, Singapore 169857, Singapore.
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Raza S, Rajak S, Yen PM, Sinha RA. Autophagy and hepatic lipid metabolism: mechanistic insight and therapeutic potential for MASLD. NPJ METABOLIC HEALTH AND DISEASE 2024; 2:19. [PMID: 39100919 PMCID: PMC11296953 DOI: 10.1038/s44324-024-00022-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 07/04/2024] [Indexed: 08/06/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) originates from a homeostatic imbalance in hepatic lipid metabolism. Increased fat deposition in the liver of people suffering from MASLD predisposes them to develop further metabolic derangements, including diabetes mellitus, metabolic dysfunction-associated steatohepatitis (MASH), and other end-stage liver diseases. Unfortunately, only limited pharmacological therapies exist for MASLD to date. Autophagy, a cellular catabolic process, has emerged as a primary mechanism of lipid metabolism in mammalian hepatocytes. Furthermore, preclinical studies with autophagy modulators have shown promising results in resolving MASLD and mitigating its progress into deleterious liver pathologies. In this review, we discuss our current understanding of autophagy-mediated hepatic lipid metabolism, its therapeutic modulation for MASLD treatment, and current limitations and scope for clinical translation.
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Affiliation(s)
- Sana Raza
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014 India
| | - Sangam Rajak
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014 India
| | - Paul M. Yen
- Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore, 169857 Singapore
| | - Rohit A. Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014 India
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9
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Tavakoli R, Maleki MH, Vakili O, Taghizadeh M, Zal F, Shafiee SM. Bilirubin, once a toxin but now an antioxidant alleviating non-alcoholic fatty liver disease in an autophagy-dependent manner in high-fat diet-induced rats: a molecular and histopathological analysis. Res Pharm Sci 2024; 19:475-488. [PMID: 39399727 PMCID: PMC11468170 DOI: 10.4103/rps.rps_53_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 06/30/2024] [Accepted: 07/07/2024] [Indexed: 10/15/2024] Open
Abstract
Background and purpose As an endogenous antioxidant, bilirubin has surprisingly been inversely correlated with the risk of non-alcoholic fatty liver disease (NAFLD). Thereupon, the current evaluation was designed to assess the positive effects of bilirubin on the autophagy flux, as well as the other pathogenic processes and parameters involved in the expansion of NAFLD. Experimental approach Thirty adult male rats weighing 150-200 g with free access to sucrose solution (18%) were randomly subdivided into 5 groups (n = 6). Subsequently, the animals were euthanized, and their blood specimens and liver tissue samples were collected to measure serum biochemical indices, liver histopathological changes, intrahepatic triglycerides content, and tissue stereological alterations. Furthermore, the expression levels of autophagy-related genes (Atgs) were measured to assess the state of the autophagy flux. Findings/Results Fasting blood glucose, body weight, as well as liver weight, liver-specific enzyme activity, and serum lipid profile indices markedly decreased in rats that underwent a six-week bilirubin treatment compared to the control group. In addition, histopathological studies showed that hepatic steatosis, fibrosis, inflammation, and necrosis significantly decreased in the groups that received bilirubin compared to the control animals. Bilirubin also caused significant alterations in the expression levels of the Atgs, as well as the Beclin- 1 protein. Conclusion and implication Bilirubin may have potential ameliorative effects on NAFLD-associated liver damage. Moreover, the beneficial effects of bilirubin on intrahepatic lipid accumulation and steatosis were comparable with the group that did not ever receive bilirubin.
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Affiliation(s)
- Ramin Tavakoli
- Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Hasan Maleki
- Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Motahareh Taghizadeh
- Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Fatemeh Zal
- Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sayed Mohammad Shafiee
- Autophagy Research Center, Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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10
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Deng P, Fan T, Gao P, Peng Y, Li M, Li J, Qin M, Hao R, Wang L, Li M, Zhang L, Chen C, He M, Lu Y, Ma Q, Luo Y, Tian L, Xie J, Chen M, Xu S, Zhou Z, Yu Z, Pi H. SIRT5-Mediated Desuccinylation of RAB7A Protects Against Cadmium-Induced Alzheimer's Disease-Like Pathology by Restoring Autophagic Flux. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2402030. [PMID: 38837686 PMCID: PMC11321632 DOI: 10.1002/advs.202402030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 05/13/2024] [Indexed: 06/07/2024]
Abstract
Cadmium (Cd) is a neurotoxic contaminant that induces cognitive decline similar to that observed in Alzheimer's disease (AD). Autophagic flux dysfunction is attributed to the pathogenesis of AD, and this study aimed to investigate the effect of autophagy on environmental Cd-induced AD progression and the underlying mechanism. Here, Cd exposure inhibited autophagosome-lysosome fusion and impaired lysosomal function, leading to defects in autophagic clearance and then to APP accumulation and nerve cell death. Proteomic analysis coupled with Ingenuity Pathway Analysis (IPA) identified SIRT5 as an essential molecular target in Cd-impaired autophagic flux. Mechanistically, Cd exposure hampered the expression of SIRT5, thus increasing the succinylation of RAB7A at lysine 31 and inhibiting RAB7A activity, which contributed to autophagic flux blockade. Importantly, SIRT5 overexpression led to the restoration of autophagic flux blockade, the alleviation of Aβ deposition and memory deficits, and the desuccinylation of RAB7A in Cd-exposed FAD4T mice. Additionally, SIRT5 levels decrease mainly in neurons but not in other cell clusters in the brains of AD patients according to single-nucleus RNA sequencing data from the public dataset GSE188545. This study reveals that SIRT5-catalysed RAB7A desuccinylation is an essential adaptive mechanism for the amelioration of Cd-induced autophagic flux blockade and AD-like pathogenesis.
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Affiliation(s)
- Ping Deng
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education)Army Medical University (Third Military Medical University)Chongqing400038China
| | - Tengfei Fan
- Department of Oral and Maxillofacial SurgeryThe Second Xiangya Hospital of Central South UniversityChangshaHunan410007China
| | - Peng Gao
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education)Army Medical University (Third Military Medical University)Chongqing400038China
| | - Yongchun Peng
- Department of Oral and Maxillofacial SurgeryThe Second Xiangya Hospital of Central South UniversityChangshaHunan410007China
| | - Min Li
- Basic Medical LaboratoryGeneral Hospital of Central Theater CommandWuhan430070China
- Hubei Key Laboratory of Central Nervous System Tumour and InterventionWuhan430070China
| | - Jingdian Li
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education)Army Medical University (Third Military Medical University)Chongqing400038China
| | - Mingke Qin
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education)Army Medical University (Third Military Medical University)Chongqing400038China
| | - Rongrong Hao
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education)Army Medical University (Third Military Medical University)Chongqing400038China
| | - Liting Wang
- Biomedical Analysis CenterArmy Medical UniversityChongqing400038China
| | - Min Li
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education)Army Medical University (Third Military Medical University)Chongqing400038China
| | - Lei Zhang
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education)Army Medical University (Third Military Medical University)Chongqing400038China
| | - Chunhai Chen
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education)Army Medical University (Third Military Medical University)Chongqing400038China
| | - Mindi He
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education)Army Medical University (Third Military Medical University)Chongqing400038China
| | - Yonghui Lu
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education)Army Medical University (Third Military Medical University)Chongqing400038China
| | - Qinlong Ma
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education)Army Medical University (Third Military Medical University)Chongqing400038China
| | - Yan Luo
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education)Army Medical University (Third Military Medical University)Chongqing400038China
| | - Li Tian
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education)Army Medical University (Third Military Medical University)Chongqing400038China
| | - Jia Xie
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education)Army Medical University (Third Military Medical University)Chongqing400038China
| | - Mengyan Chen
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education)Army Medical University (Third Military Medical University)Chongqing400038China
| | - Shangcheng Xu
- Center of Laboratory MedicineChongqing Prevention and Treatment Center for Occupational DiseasesChongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and PoisoningChongqing400060China
| | - Zhou Zhou
- Center for Neuro IntelligenceSchool of MedicineChongqing UniversityChongqing400030China
| | - Zhengping Yu
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education)Army Medical University (Third Military Medical University)Chongqing400038China
| | - Huifeng Pi
- Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education)Army Medical University (Third Military Medical University)Chongqing400038China
- State Key Laboratory of Trauma and Chemical PoisoningArmy Medical UniversityChongqing400038China
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11
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Zhou S, Taskintuna K, Hum J, Gulati J, Olaya S, Steinman J, Golestaneh N. PGC-1α repression dysregulates lipid metabolism and induces lipid droplet accumulation in retinal pigment epithelium. Cell Death Dis 2024; 15:385. [PMID: 38824126 PMCID: PMC11144268 DOI: 10.1038/s41419-024-06762-y] [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: 05/15/2023] [Revised: 05/16/2024] [Accepted: 05/20/2024] [Indexed: 06/03/2024]
Abstract
Drusen, the yellow deposits under the retina, are composed of lipids and proteins, and represent a hallmark of age-related macular degeneration (AMD). Lipid droplets are also reported in the retinal pigment epithelium (RPE) from AMD donor eyes. However, the mechanisms underlying these disease phenotypes remain elusive. Previously, we showed that Pgc-1α repression, combined with a high-fat diet (HFD), induce drastic AMD-like phenotypes in mice. We also reported increased PGC-1α acetylation and subsequent deactivation in the RPE derived from AMD donor eyes. Here, through a series of in vivo and in vitro experiments, we sought to investigate the molecular mechanisms by which PGC-1α repression could influence RPE and retinal function. We show that PGC-1α plays an important role in RPE and retinal lipid metabolism and function. In mice, repression of Pgc-1α alone induced RPE and retinal degeneration and drusen-like deposits. In vitro inhibition of PGC1A by CRISPR-Cas9 gene editing in human RPE (ARPE19- PGC1A KO) affected the expression of genes responsible for lipid metabolism, fatty acid β-oxidation (FAO), fatty acid transport, low-density lipoprotein (LDL) uptake, cholesterol esterification, cholesterol biosynthesis, and cholesterol efflux. Moreover, inhibition of PGC1A in RPE cells caused lipid droplet accumulation and lipid peroxidation. ARPE19-PGC1A KO cells also showed reduced mitochondrial biosynthesis, impaired mitochondrial dynamics and activity, reduced antioxidant enzymes, decreased mitochondrial membrane potential, loss of cardiolipin, and increased susceptibility to oxidative stress. Our data demonstrate the crucial role of PGC-1α in regulating lipid metabolism. They provide new insights into the mechanisms involved in lipid and drusen accumulation in the RPE and retina during aging and AMD, which may pave the way for developing novel therapeutic strategies targeting PGC-1α.
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Affiliation(s)
- Shuyan Zhou
- Department of Ophthalmology, Georgetown University Medical Center, Washington, DC, 20007, USA
| | - Kaan Taskintuna
- Department of Ophthalmology, Georgetown University Medical Center, Washington, DC, 20007, USA
| | - Jacob Hum
- Department of Ophthalmology, Georgetown University Medical Center, Washington, DC, 20007, USA
| | - Jasmine Gulati
- Department of Ophthalmology, Georgetown University Medical Center, Washington, DC, 20007, USA
| | - Stephanie Olaya
- Department of Ophthalmology, Georgetown University Medical Center, Washington, DC, 20007, USA
| | - Jeremy Steinman
- Department of Ophthalmology, Georgetown University Medical Center, Washington, DC, 20007, USA
| | - Nady Golestaneh
- Department of Ophthalmology, Georgetown University Medical Center, Washington, DC, 20007, USA.
- Department of Neurology, Georgetown University Medical Center, Washington, DC, 20007, USA.
- Department of Biochemistry and Molecular & Cellular Biology, Washington, DC, 20007, USA.
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12
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Kim D, Ha SK, Gonzalez FJ. CBFA2T3 Is PPARA Sensitive and Attenuates Fasting-Induced Lipid Accumulation in Mouse Liver. Cells 2024; 13:831. [PMID: 38786053 PMCID: PMC11119203 DOI: 10.3390/cells13100831] [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: 04/09/2024] [Revised: 05/10/2024] [Accepted: 05/10/2024] [Indexed: 05/25/2024] Open
Abstract
Peroxisome proliferator-activated receptor alpha (PPARA) is a ligand-activated transcription factor that is a key mediator of lipid metabolism and metabolic stress in the liver. Accumulating evidence shows that PPARA regulates the expression of various protein coding and non-coding genes that modulate metabolic stress in the liver. CBFA2/RUNX1 partner transcriptional co-repressor 3 (CBFA2T3) is a DNA-binding transcription factor that belongs to the myeloid translocation gene family. Many studies have shown that CBFA2T3 is associated with acute myeloid leukemia. Especially, CBFA2T3-GLIS2 fusion is a chimeric oncogene associated with a poor survival rate in pediatric acute megakaryocytic leukemia. A previous study identified that PPARA activation promoted Cbfa2t3 induction in liver and that Cbfa2t3 may have a modulatory role in metabolic stress. However, the effect of CBFA2T3 gene expression on metabolic stress is not understood. In this study, the PPARA ligand WY14643 activated Cbfa2t3 expression in mouse liver. Glucose tolerance test and insulin tolerance test data showed that insulin resistance is increased in Cbfa2t3-/- mice compared to Cbfa2t3+/+ mice. Hepatic CBFA2T3 modulates heat shock protein family A member 1b and carbonic anhydrase 5a expression. Histology analysis revealed lipid droplet and lipid accumulation in the liver of fasting Cbfa2t3-/- mice but not Cbfa2t3+/+ mice. The expression of lipid accumulation-related genes, such as Cd36, Cidea, and Fabp1, was increased in the liver of fasting Cbfa2t3-/- mice. Especially, basal expression levels of Cidea mRNA were elevated in the liver of Cbfa2t3-/- mice compared to Cbfa2t3+/+ mice. Much higher induction of Cidea mRNA was seen in the liver of Cbfa2t3-/- mice after WY14643 administration. These results indicate that hepatic CBFA2T3 is a PPARA-sensitive gene that may modulate metabolic stress in mouse liver.
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Affiliation(s)
- Donghwan Kim
- Division of Functional Food Research, Korea Food Research Institute, Wanju-gun 55365, Republic of Korea;
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Sang Keun Ha
- Division of Functional Food Research, Korea Food Research Institute, Wanju-gun 55365, Republic of Korea;
- Division of Food Biotechnology, University of Science and Technology, Daejeon 34113, Republic of Korea
| | - Frank J. Gonzalez
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;
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13
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López CAM, Freiberger RN, Sviercz FA, Jarmoluk P, Cevallos C, Quarleri J, Delpino MV. HIV and gp120-induced lipid droplets loss in hepatic stellate cells contribute to profibrotic profile. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167084. [PMID: 38368823 DOI: 10.1016/j.bbadis.2024.167084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/24/2024] [Accepted: 02/12/2024] [Indexed: 02/20/2024]
Abstract
Liver fibrosis is the excessive accumulation of extracellular matrix proteins, primarily collagen, in response to liver injury caused by chronic liver diseases. HIV infection accelerates the progression of liver fibrosis in patients co-infected with HCV or HBV compared to those who are only mono-infected. The early event in the progression of liver fibrosis involves the activation of hepatic stellate cells (HSCs), which entails the loss of lipid droplets (LD) to fuel the production of extracellular matrix components crucial for liver tissue healing. Thus, we are examining the mechanism by which HIV stimulates the progression of liver fibrosis. HIV-R5 tropic infection was unable to induce the expression of TGF-β, collagen deposition, α-smooth muscle actin (α-SMA), and cellular proliferation. However, this infection induced the secretion of the profibrogenic cytokine IL-6 and the loss of LD. This process involved the participation of peroxisome proliferator-activated receptor (PPAR)-α and an increase in lysosomal acid lipase (LAL), along with the involvement of Microtubule-associated protein 1 A/1B-light chain 3 (LC3), strongly suggesting that LD loss could occur through acid lipolysis. These phenomena were mimicked by the gp120 protein from the R5 tropic strain of HIV. Preincubation of HSCs with the CCR5 receptor antagonist, TAK-779, blocked gp120 activity. Additionally, experiments performed with pseudotyped-HIV revealed that HIV replication could also contribute to LD loss. These results demonstrate that the cross-talk between HSCs and HIV involves a series of interactions that help explain some of the mechanisms involved in the exacerbation of liver damage observed in co-infected individuals.
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Affiliation(s)
- Cinthya Alicia Marcela López
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Consejo de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Rosa Nicole Freiberger
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Consejo de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Franco Agustín Sviercz
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Consejo de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Patricio Jarmoluk
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Consejo de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Cintia Cevallos
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Consejo de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Jorge Quarleri
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Consejo de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - María Victoria Delpino
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), Facultad de Medicina, Consejo de Investigaciones Científicas y Técnicas (CONICET), Universidad de Buenos Aires, Buenos Aires, Argentina.
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14
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Yang Y, Qiu W, Xiao J, Sun J, Ren X, Jiang L. Dihydromyricetin ameliorates hepatic steatosis and insulin resistance via AMPK/PGC-1α and PPARα-mediated autophagy pathway. J Transl Med 2024; 22:309. [PMID: 38532480 PMCID: PMC10964712 DOI: 10.1186/s12967-024-05060-7] [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: 09/27/2023] [Accepted: 03/04/2024] [Indexed: 03/28/2024] Open
Abstract
BACKGROUND Dihydromyricetin (DHM), a flavonoid compound of natural origin, has been identified in high concentrations in ampelopsis grossedentata and has a broad spectrum of biological and pharmacological functions, particularly in regulating glucose and lipid metabolism. The objective of this research was to examine how DHM affected nonalcoholic fatty liver disease (NAFLD) and its underlying mechanisms involved in the progression of NAFLD in a rat model subjected to a high-fat diet (HFD). Additionally, the study examines the underlying mechanisms in a cellular model of steatohepatitis using palmitic acid (PA)-treated HepG2 cells, with a focus on the potential correlation between autophagy and hepatic insulin resistance (IR) in the progress of NAFLD. METHODS SD rats were exposed to a HFD for a period of eight weeks, followed by a treatment with DHM (at doses of 50, 100, and 200 mg·kg-1·d-1) for additional six weeks. The HepG2 cells received a 0.5 mM PA treatment for 24 h, either alone or in conjunction with DHM (10 µM). The histopathological alterations were assessed by the use of Hematoxylin-eosin (H&E) staining. The quantification of glycogen content and lipid buildup in the liver was conducted by the use of PAS and Oil Red O staining techniques. Serum lipid and liver enzyme levels were also measured. Autophagic vesicle and autolysosome morphology was studied using electron microscopy. RT-qPCR and/or western blotting techniques were used to measure IR- and autophagy-related factors levels. RESULTS The administration of DHM demonstrated efficacy in ameliorating hepatic steatosis, as seen in both in vivo and in vitro experimental models. Moreover, DHM administration significantly increased GLUT2 expression, decreased G6Pase and PEPCK expression, and improved IR in the hepatic tissue of rats fed a HFD and in cells exhibiting steatosis. DHM treatment elevated Beclin 1, ATG 5, and LC3-II levels in hepatic steatosis models, correlating with autolysosome formation. The expression of AMPK levels and its downstream target PGC-1α, and PPARα were decreased in HFD-fed rats and PA-treated hepatocytes, which were reversed through DHM treatment. AMPK/ PGC-1α and PPARα knockdown reduced the impact of DHM on hepatic autophagy, IR and accumulation of hepatic lipid. CONCLUSIONS Our findings revealed that AMPK/ PGC-1α, PPARα-dependent autophagy pathways in the pathophysiology of IR and hepatic steatosis has been shown, suggesting that DHM might potentially serve as a promising treatment option for addressing this disease.
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Affiliation(s)
- Yan Yang
- Department of Endocrinology and Metabolism, Lanzhou University Second Hospital, Lanzhou, China
| | - Wen Qiu
- Department of Pharmacology, Lanzhou University Second Hospital, Lanzhou, China
| | - Jiyuan Xiao
- Department of Pharmacology, Lanzhou University Second Hospital, Lanzhou, China
| | - Jie Sun
- Department of Endocrinology and Metabolism, Lanzhou University Second Hospital, Lanzhou, China
| | - Xuan Ren
- Department of Endocrinology and Metabolism, Lanzhou University Second Hospital, Lanzhou, China
| | - Luxia Jiang
- Department of Cardiac Surgery ICU, Lanzhou University Second Hospital, Lanzhou, China.
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15
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Sinha RA. Targeting nuclear receptors for NASH/MASH: From bench to bedside. LIVER RESEARCH (BEIJING, CHINA) 2024; 8:34-45. [PMID: 38544909 PMCID: PMC7615772 DOI: 10.1016/j.livres.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 11/27/2023] [Accepted: 03/07/2024] [Indexed: 04/17/2024]
Abstract
The onset of metabolic dysfunction-associated steatohepatitis (MASH) or non-alcoholic steatohepatitis (NASH) represents a tipping point leading to liver injury and subsequent hepatic complications in the natural progression of what is now termed metabolic dysfunction-associated steatotic liver diseases (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD). With no pharmacological treatment currently available for MASH/NASH, the race is on to develop drugs targeting multiple facets of hepatic metabolism, inflammation, and pro-fibrotic events, which are major drivers of MASH. Nuclear receptors (NRs) regulate genomic transcription upon binding to lipophilic ligands and govern multiple aspects of liver metabolism and inflammation. Ligands of NRs may include hormones, lipids, bile acids, and synthetic ligands, which upon binding to NRs regulate the transcriptional activities of target genes. NR ligands are presently the most promising drug candidates expected to receive approval from the United States Food and Drug Administration as a pharmacological treatment for MASH. This review aims to cover the current understanding of NRs, including nuclear hormone receptors, non-steroid hormone receptors, circadian NRs, and orphan NRs, which are currently undergoing clinical trials for MASH treatment, along with NRs that have shown promising results in preclinical studies.
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Affiliation(s)
- Rohit A. Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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16
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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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17
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Hu Y, Wang R, Liu J, Wang Y, Dong J. Lipid droplet deposition in the regenerating liver: A promoter, inhibitor, or bystander? Hepatol Commun 2023; 7:e0267. [PMID: 37708445 PMCID: PMC10503682 DOI: 10.1097/hc9.0000000000000267] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 07/29/2023] [Indexed: 09/16/2023] Open
Abstract
Liver regeneration (LR) is a complex process involving intricate networks of cellular connections, cytokines, and growth factors. During the early stages of LR, hepatocytes accumulate lipids, primarily triacylglycerol, and cholesterol esters, in the lipid droplets. Although it is widely accepted that this phenomenon contributes to LR, the impact of lipid droplet deposition on LR remains a matter of debate. Some studies have suggested that lipid droplet deposition has no effect or may even be detrimental to LR. This review article focuses on transient regeneration-associated steatosis and its relationship with the liver regenerative response.
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Affiliation(s)
- Yuelei Hu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Ruilin Wang
- Department of Cadre’s Wards Ultrasound Diagnostics. Ultrasound Diagnostic Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Juan Liu
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing, China
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing, China
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Yunfang Wang
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing, China
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing, China
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Jiahong Dong
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing, China
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- Institute for Organ Transplant and Bionic Medicine, Tsinghua University, Beijing, China
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18
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Darci-Maher N, Alvarez M, Arasu UT, Selvarajan I, Lee SHT, Pan DZ, Miao Z, Das SS, Kaminska D, Örd T, Benhammou JN, Wabitsch M, Pisegna JR, Männistö V, Pietiläinen KH, Laakso M, Sinsheimer JS, Kaikkonen MU, Pihlajamäki J, Pajukanta P. Cross-tissue omics analysis discovers ten adipose genes encoding secreted proteins in obesity-related non-alcoholic fatty liver disease. EBioMedicine 2023; 92:104620. [PMID: 37224770 PMCID: PMC10277924 DOI: 10.1016/j.ebiom.2023.104620] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 04/14/2023] [Accepted: 05/03/2023] [Indexed: 05/26/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a fast-growing, underdiagnosed, epidemic. We hypothesise that obesity-related inflammation compromises adipose tissue functions, preventing efficient fat storage, and thus driving ectopic fat accumulation into the liver. METHODS To identify adipose-based mechanisms and potential serum biomarker candidates (SBCs) for NAFLD, we utilise dual-tissue RNA-sequencing (RNA-seq) data in adipose tissue and liver, paired with histology-based NAFLD diagnosis, from the same individuals in a cohort of obese individuals. We first scan for genes that are differentially expressed (DE) for NAFLD in obese individuals' subcutaneous adipose tissue but not in their liver; encode proteins secreted to serum; and show preferential adipose expression. Then the identified genes are filtered to key adipose-origin NAFLD genes by best subset analysis, knockdown experiments during human preadipocyte differentiation, recombinant protein treatment experiments in human liver HepG2 cells, and genetic analysis. FINDINGS We discover a set of genes, including 10 SBCs, that may modulate NAFLD pathogenesis by impacting adipose tissue function. Based on best subset analysis, we further follow-up on two SBCs CCDC80 and SOD3 by knockdown in human preadipocytes and subsequent differentiation experiments, which show that they modulate crucial adipogenesis genes, LPL, SREBPF1, and LEP. We also show that treatment of the liver HepG2 cells with the CCDC80 and SOD3 recombinant proteins impacts genes related to steatosis and lipid processing, including PPARA, NFE2L2, and RNF128. Finally, utilizing the adipose NAFLD DE gene cis-regulatory variants associated with serum triglycerides (TGs) in extensive genome-wide association studies (GWASs), we demonstrate a unidirectional effect of serum TGs on NAFLD with Mendelian Randomization (MR) analysis. We also demonstrate that a single SNP regulating one of the SBC genes, rs2845885, produces a significant MR result by itself. This supports the conclusion that genetically regulated adipose expression of the NAFLD DE genes may contribute to NAFLD through changes in serum TG levels. INTERPRETATION Our results from the dual-tissue transcriptomics screening improve the understanding of obesity-related NAFLD by providing a targeted set of 10 adipose tissue-active genes as new serum biomarker candidates for the currently grossly underdiagnosed fatty liver disease. FUNDING The work was supported by NIH grants R01HG010505 and R01DK132775. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The KOBS study (J. P.) was supported by the Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005-2019), and the Academy of Finland grant (Contract no. 138006). This study was funded by the European Research Council under the European Union's Horizon 2020 research and innovation program (Grant No. 802825 to M. U. K.). K. H. P. was funded by the Academy of Finland (grant numbers 272376, 266286, 314383, and 335443), the Finnish Medical Foundation, Gyllenberg Foundation, Novo Nordisk Foundation (grant numbers NNF10OC1013354, NNF17OC0027232, and NNF20OC0060547), Finnish Diabetes Research Foundation, Finnish Foundation for Cardiovascular Research, University of Helsinki, and Helsinki University Hospital and Government Research Funds. I. S. was funded by the Instrumentarium Science Foundation. Personal grants to U. T. A. were received from the Matti and Vappu Maukonen Foundation, Ella och Georg Ehrnrooths Stiftelse and the Finnish Foundation for Cardiovascular Research.
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Affiliation(s)
- Nicholas Darci-Maher
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Marcus Alvarez
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Uma Thanigai Arasu
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Ilakya Selvarajan
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Seung Hyuk T Lee
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - David Z Pan
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Zong Miao
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Sankha Subhra Das
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Dorota Kaminska
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Tiit Örd
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Jihane N Benhammou
- Vatche and Tamar Manoukian Division of Digestive Diseases, and Gastroenterology, Hepatology and Parenteral Nutrition, David Geffen School of Medicine at UCLA and VA Greater Los Angeles HCS, Los Angeles, USA
| | - Martin Wabitsch
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany
| | - Joseph R Pisegna
- Department of Medicine and Human Genetics, Division of Gastroenterology, Hepatology and Parenteral Nutrition, David Geffen School of Medicine at UCLA and VA Greater Los Angeles HCS, Los Angeles, USA
| | - Ville Männistö
- Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
| | - Kirsi H Pietiläinen
- Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Obesity Center, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Markku Laakso
- Institute of Clinical Medicine, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland
| | - Janet S Sinsheimer
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA; Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, USA; Department of Computational Medicine, David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - Minna U Kaikkonen
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Jussi Pihlajamäki
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
| | - Päivi Pajukanta
- Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, USA; Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, USA.
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Lian CY, Wei S, Li ZF, Zhang SH, Wang ZY, Wang L. Glyphosate-induced autophagy inhibition results in hepatic steatosis via mediating epigenetic reprogramming of PPARα in roosters. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 324:121394. [PMID: 36906059 DOI: 10.1016/j.envpol.2023.121394] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 02/15/2023] [Accepted: 03/02/2023] [Indexed: 06/18/2023]
Abstract
Glyphosate (Gly) is the most widely used herbicide with well-defined hepatotoxic effects, but the underlying mechanisms of Gly-induced hepatic steatosis remain largely unknown. In this study, a rooster model combined with primary chicken embryo hepatocytes was established to dissect the progresses and mechanisms of Gly-induced hepatic steatosis. Data showed that Gly exposure caused liver injury with disrupted lipid metabolism in roosters, manifested by significant serum lipid profile disorder and hepatic lipid accumulation. Transcriptomic analysis revealed that PPARα and autophagy-related pathways played important roles in Gly-induced hepatic lipid metabolism disorders. Further experimental results suggested that autophagy inhibition was involved in Gly-induced hepatic lipid accumulation, which was confirmed by the effect of classic autophagy inducer rapamycin (Rapa). Moreover, data substantiated that Gly-mediated autophagy inhibition caused nuclear increase of HDAC3, which altered epigenetic modification of PPARα, leading to fatty acid oxidation (FAO) inhibition and subsequently lipid accumulation in the hepatocytes. In summary, this study provides novel evidence that Gly-induced autophagy inhibition evokes the inactivation of PPARα-mediated FAO and concomitant hepatic steatosis in roosters by mediating epigenetic reprogramming of PPARα.
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Affiliation(s)
- Cai-Yu Lian
- College of Animal Science and Veterinary Medicine, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China
| | - Sheng Wei
- Experimental Center, Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong Provincial Key Laboratory of Traditional Chinese Medicine for Basic Research, Shandong University of Traditional Chinese Medicine, Ji'nan, 250355, China
| | - Zi-Fa Li
- Experimental Center, Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong Provincial Key Laboratory of Traditional Chinese Medicine for Basic Research, Shandong University of Traditional Chinese Medicine, Ji'nan, 250355, China
| | - Shu-Hui Zhang
- College of Animal Science and Veterinary Medicine, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China
| | - Zhen-Yong Wang
- College of Animal Science and Veterinary Medicine, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China
| | - Lin Wang
- College of Animal Science and Veterinary Medicine, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Provincial Engineering Technology Research Center of Animal Disease Control and Prevention, Shandong Agricultural University, 61 Daizong Street, Tai'an City, Shandong Province, 271018, China.
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20
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Vakili O, Borji M, Saffari-Chaleshtori J, Shafiee SM. Ameliorative effects of bilirubin on cell culture model of non-alcoholic fatty liver disease. Mol Biol Rep 2023; 50:4411-4422. [PMID: 36971910 DOI: 10.1007/s11033-023-08339-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 02/15/2023] [Indexed: 03/29/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is defined as the most prevalent hepatic disorder that affects a significant population worldwide. There are several genes/proteins, involving in the modulation of NAFLD pathogenesis; sirtuin1 (SIRT1), TP53-inducible regulator gene (TIGAR), and autophagy-related gene 5 (Atg5) are considered a chief group of these modulators that principally act by regulating the hepatic lipid metabolism, as well as preventing the lipid accumulation. Surprisingly, bilirubin, especially in its unconjugated form, might be able to alleviate NAFLD progression by decreasing lipid accumulation and regulating the expression levels of the above-stated genes. METHODS AND RESULTS Herein, the interactions between bilirubin and the corresponding genes' products were first analyzed by docking assessments. Afterwards, HepG2 cells were cultured under the optimum conditions, and then were incubated with high concentrations of glucose to induce NAFLD. After treating normal and fatty liver cells with particular bilirubin concentrations for 24- and 48-hour periods, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay, colorimetric method, and quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) were employed to assess cell viability status, intracellular triglycerides content, and mRNA expression levels of the genes, respectively. Intracellular lipid accumulation of HepG2 cells was significantly decreased after treating with bilirubin. Bilirubin also increased SIRT1 and Atg5 gene expression levels in fatty liver cells. TIGAR gene expression levels were variable upon the conditions and the cell type, suggesting a dual role for TIGAR during the NAFLD pathogenesis. CONCLUSION Our findings indicate the potential of bilirubin in the prevention from or amelioration of NAFLD through influencing SIRT1-related deacetylation and the process of lipophagy, as well as decreasing the intrahepatic lipid content. In vitro model of NAFLD was treated with unconjugated bilirubin under the optimal conditions.Desirably, bilirubin moderated the accumulation of triglycerides within the cells possibly through modulation of the expression of SIRT1, Atg5, and TIGAR genes. In the context, bilirubin was shown to increase the expression levels of SIRT1 and Atg5, while the expression of TIGAR was demonstrated to be either increased or decreased, depending on the treatment conditions. Created with BioRender.com.
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Tan S, Ke Z, Zhou C, Luo Y, Ding X, Luo G, Li W, Shi S. Polyphenol Profile, Antioxidant Activity, and Hypolipidemic Effect of Longan Byproducts. Molecules 2023; 28:molecules28052083. [PMID: 36903329 PMCID: PMC10004001 DOI: 10.3390/molecules28052083] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 02/10/2023] [Accepted: 02/20/2023] [Indexed: 02/25/2023] Open
Abstract
Longan, a popular fruit in Asia, has been used in traditional Chinese medicine to treat several diseases for centuries. Recent studies have indicated that longan byproducts are rich in polyphenols. The aim of this study was to analyze the phenolic composition of longan byproduct polyphenol extracts (LPPE), evaluate their antioxidant activity in vitro, and investigate their regulating effect on lipid metabolism in vivo. The results indicated that the antioxidant activity of LPPE was 231.350 ± 21.640, 252.380 ± 31.150, and 558.220 ± 59.810 (mg Vc/g) as determined by DPPH, ABTS, and FRAP, respectively. UPLC-QqQ-MS/MS analysis indicated that the main compounds in LPPE were gallic acid, proanthocyanidin, epicatechin, and phlorizin. LPPE supplementation prevented the body weight gain and decreased serum and liver lipids in high-fat diet-induced-obese mice. Furthermore, RT-PCR and Western blot analysis indicated that LPPE upregulated the expression of PPARα and LXRα and then regulated their target genes, including FAS, CYP7A1, and CYP27A1, which are involved in lipid homeostasis. Taken together, this study supports the concept that LPPE can be used as a dietary supplement in regulating lipid metabolism.
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Affiliation(s)
- Si Tan
- School of Advanced Agriculture and Bioengineering, Yangtze Normal University, Chongqing 408100, China
- South Subtropical Crops Research Institute, Chinese Academy of Tropical Agricultural Sciences, Zhanjiang 524091, China
- Correspondence: (S.T.); (S.S.)
| | - Zunli Ke
- Basic Medical School, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China
| | - Chongbing Zhou
- School of Advanced Agriculture and Bioengineering, Yangtze Normal University, Chongqing 408100, China
| | - Yuping Luo
- School of Advanced Agriculture and Bioengineering, Yangtze Normal University, Chongqing 408100, China
| | - Xiaobo Ding
- Luzhou Academy of Agricultural Sciences, Luzhou 646000, China
| | - Gangjun Luo
- School of Advanced Agriculture and Bioengineering, Yangtze Normal University, Chongqing 408100, China
| | - Wenfeng Li
- School of Advanced Agriculture and Bioengineering, Yangtze Normal University, Chongqing 408100, China
| | - Shengyou Shi
- School of Advanced Agriculture and Bioengineering, Yangtze Normal University, Chongqing 408100, China
- South Subtropical Crops Research Institute, Chinese Academy of Tropical Agricultural Sciences, Zhanjiang 524091, China
- Correspondence: (S.T.); (S.S.)
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22
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Park M, Sharma A, Baek H, Han JY, Yu J, Lee HJ. Stevia and Stevioside Attenuate Liver Steatosis through PPARα-Mediated Lipophagy in db/db Mice Hepatocytes. Antioxidants (Basel) 2022; 11:antiox11122496. [PMID: 36552704 PMCID: PMC9774531 DOI: 10.3390/antiox11122496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 12/01/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Lipophagy, a type of autophagy that breaks down lipid droplets, is essential in the regulation of intracellular lipid accumulation and intracellular free fatty acid levels in numerous organisms and metabolic conditions. We investigated the effects of Stevia rebaudiana Bertoni (S), a low-calorie sweetener, and stevioside (SS) on hepatic steatosis and autophagy in hepatocytes, as well as in db/db mice. S and SS reduced the body and liver weight and levels of serum triglyceride, total cholesterol, and hepatic lipogenic proteins. In addition, S and SS increased the levels of fatty acid oxidase, peroxisome proliferator-activated receptor alpha (PPARα), and microtubule-associated protein light chain 3 B but decreased that of sequestosome 1 (p62) in the liver of db/db mice. Additionally, Beclin 1, lysosomal associated membrane protein 1, and phosphorylated adenosine monophosphate-activated protein kinase protein expression was augmented following S and SS treatment of db/db mice. Furthermore, the knockdown of PPARα blocked lipophagy in response to SS treatment in HepG2 cells. These outcomes indicate that PPARα-dependent lipophagy is involved in hepatic steatosis in the db/db mouse model and that SS, a PPARα agonist, represents a new therapeutic option for managing associated diseases.
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Affiliation(s)
- Miey Park
- Department of Food and Nutrition, College of BioNano Technology, Gachon University, Seongnam 13120, Gyeonggi-do, Republic of Korea
- Institute for Aging and Clinical Nutrition Research, Gachon University, Seongnam 13120, Gyeonggi-do, Republic of Korea
| | - Anshul Sharma
- Department of Food and Nutrition, College of BioNano Technology, Gachon University, Seongnam 13120, Gyeonggi-do, Republic of Korea
| | - Hana Baek
- Department of Food and Nutrition, College of BioNano Technology, Gachon University, Seongnam 13120, Gyeonggi-do, Republic of Korea
- Institute for Aging and Clinical Nutrition Research, Gachon University, Seongnam 13120, Gyeonggi-do, Republic of Korea
| | - Jin-Young Han
- Institute for Aging and Clinical Nutrition Research, Gachon University, Seongnam 13120, Gyeonggi-do, Republic of Korea
| | - Junho Yu
- Department of Food and Nutrition, College of BioNano Technology, Gachon University, Seongnam 13120, Gyeonggi-do, Republic of Korea
- Institute for Aging and Clinical Nutrition Research, Gachon University, Seongnam 13120, Gyeonggi-do, Republic of Korea
| | - Hae-Jeung Lee
- Department of Food and Nutrition, College of BioNano Technology, Gachon University, Seongnam 13120, Gyeonggi-do, Republic of Korea
- Institute for Aging and Clinical Nutrition Research, Gachon University, Seongnam 13120, Gyeonggi-do, Republic of Korea
- Correspondence: or ; Tel.: +82-31-750-5968; Fax: +82-31-724-4411
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23
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Chhimwal J, Goel A, Sukapaka M, Patial V, Padwad Y. Phloretin mitigates oxidative injury, inflammation, and fibrogenic responses via restoration of autophagic flux in in vitro and preclinical models of NAFLD. J Nutr Biochem 2022; 107:109062. [PMID: 35609858 DOI: 10.1016/j.jnutbio.2022.109062] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 04/11/2022] [Accepted: 04/20/2022] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) with growing incidences is a major health concern worldwide. Alteration in cellular redox homeostasis and autophagy plays a critical role in the progression of NAFLD to more severe outcomes. The lack of safe and effective therapy for the disease necessitates the exploration of new therapeutic compounds. Therefore, in the present study, we investigated the potential of phloretin to maintain redox equilibrium and prevent disease progression via modulation of autophagy in NAFLD. Free fatty acid exposed Huh7 cells were used to evaluate the efficacy of phloretin in vitro. Further, phloretin was administered orally to western diet induced NAFLD in C57BL/6J mice at different doses. The chronic exposure to fatty acids and the western diet triggered lipid accumulation in the Huh7 cells and western diet-fed mice liver, respectively. In addition, mitochondrial dysfunction, oxidative stress, inflammation and decreased hepatic autophagy were observed in disease condition. Phloretin encouraged autophagy mediated hepatic lipid clearance and restored mitochondrial membrane potential and redox homeostasis. It also reduced histological injury by reducing hepatic lipogenesis and facilitating fatty acid oxidation. Moreover, findings of the study also revealed the mitigatory effect of phloretin on inflammatory and fibrogenic markers. Altogether, the study suggested that phloretin effectively attenuates NAFLD progression via upregulating autophagy-mediated lipid breakdown and inhibits oxidative damage, hepatic inflammation and fibrosis.
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Affiliation(s)
- Jyoti Chhimwal
- Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad - 201002, India
| | - Abhishek Goel
- Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad - 201002, India
| | - Mahesh Sukapaka
- Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India
| | - Vikram Patial
- Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad - 201002, India.
| | - Yogendra Padwad
- Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad - 201002, India.
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24
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Przybycień P, Gąsior-Perczak D, Placha W. Cannabinoids and PPAR Ligands: The Future in Treatment of Polycystic Ovary Syndrome Women with Obesity and Reduced Fertility. Cells 2022; 11:cells11162569. [PMID: 36010645 PMCID: PMC9406585 DOI: 10.3390/cells11162569] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 08/13/2022] [Accepted: 08/17/2022] [Indexed: 11/21/2022] Open
Abstract
Cannabinoids (CBs) are used to treat chronic pain, chemotherapy-induced nausea and vomiting, and multiple sclerosis spasticity. Recently, the medicinal use of CBs has attracted increasing interest as a new therapeutic in many diseases. Data indicate a correlation between CBs and PPARs via diverse mechanisms. Both the endocannabinoid system (ECS) and peroxisome proliferator-activated receptors (PPARs) may play a significant role in PCOS and PCOS related disorders, especially in disturbances of glucose-lipid metabolism as well as in obesity and fertility. Taking into consideration the ubiquity of PCOS in the human population, it seems indispensable to search for new potential therapeutic targets for this condition. The aim of this review is to examine the relationship between metabolic disturbances and obesity in PCOS pathology. We discuss current and future therapeutic interventions for PCOS and related disorders, with emphasis on the metabolic pathways related to PCOS pathophysiology. The link between the ECS and PPARs is a promising new target for PCOS, and we examine this relationship in depth.
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Affiliation(s)
- Piotr Przybycień
- Chair of Medical Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, 31-034 Krakow, Poland
- Endocrinology Clinic, Holycross Cancer Centre, 25-734 Kielce, Poland
| | - Danuta Gąsior-Perczak
- Endocrinology Clinic, Holycross Cancer Centre, 25-734 Kielce, Poland
- Collegium Medicum, Jan Kochanowski University, 25-317 Kielce, Poland
| | - Wojciech Placha
- Chair of Medical Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, 31-034 Krakow, Poland
- Correspondence: ; Tel.: +48-12-422-74-00
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Rajak S, Raza S, Sinha RA. ULK1 Signaling in the Liver: Autophagy Dependent and Independent Actions. Front Cell Dev Biol 2022; 10:836021. [PMID: 35252196 PMCID: PMC8894804 DOI: 10.3389/fcell.2022.836021] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/04/2022] [Indexed: 12/18/2022] Open
Abstract
Liver is the primary organ for energy metabolism and detoxification in the human body. Not surprisingly, a derangement in liver function leads to several metabolic diseases. Autophagy is a cellular process, which primarily deals with providing molecules for energy production, and maintains cellular health. Autophagy in the liver has been implicated in several hepatic metabolic processes, such as, lipolysis, glycogenolysis, and gluconeogenesis. Autophagy also provides protection against drugs and pathogens. Deregulation of autophagy is associated with the development of non-alcoholic fatty liver disease (NAFLD) acute-liver injury, and cancer. The process of autophagy is synchronized by the action of autophagy family genes or autophagy (Atg) genes that perform key functions at different steps. The uncoordinated-51-like kinases 1 (ULK1) is a proximal kinase member of the Atg family that plays a crucial role in autophagy. Interestingly, ULK1 actions on hepatic cells may also involve some autophagy-independent signaling. In this review, we provide a comprehensive update of ULK1 mediated hepatic action involving lipotoxicity, acute liver injury, cholesterol synthesis, and hepatocellular carcinoma, including both its autophagic and non-autophagic functions.
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Affiliation(s)
| | | | - Rohit Anthony Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Transcriptional Regulation of Hepatic Autophagy by Nuclear Receptors. Cells 2022; 11:cells11040620. [PMID: 35203271 PMCID: PMC8869834 DOI: 10.3390/cells11040620] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 02/07/2022] [Accepted: 02/08/2022] [Indexed: 02/04/2023] Open
Abstract
Autophagy is an adaptive self-eating process involved in degradation of various cellular components such as carbohydrates, lipids, proteins, and organelles. Its activity plays an essential role in tissue homeostasis and systemic metabolism in response to diverse challenges, including nutrient depletion, pathogen invasion, and accumulations of toxic materials. Therefore, autophagy dysfunctions are intimately associated with many human diseases such as cancer, neurodegeneration, obesity, diabetes, infection, and aging. Although its acute post-translational regulation is well described, recent studies have also shown that autophagy can be controlled at the transcriptional and post-transcriptional levels. Nuclear receptors (NRs) are in general ligand-dependent transcription factors consisting of 48 members in humans. These receptors extensively control transcription of a variety of genes involved in development, metabolism, and inflammation. In this review, we discuss the roles and mechanisms of NRs in an aspect of transcriptional regulation of hepatic autophagy, and how the NR-driven autophagy pathway can be harnessed to treat various liver diseases.
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Yagai T, Nakamura T. Mechanistic insights into the peroxisome proliferator-activated receptor alpha as a transcriptional suppressor. Front Med (Lausanne) 2022; 9:1060244. [PMID: 36507526 PMCID: PMC9732035 DOI: 10.3389/fmed.2022.1060244] [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: 10/03/2022] [Accepted: 11/08/2022] [Indexed: 11/27/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent hepatic disorders that 20-30% of the world population suffers from. The feature of NAFLD is excess lipid accumulation in the liver, exacerbating multiple metabolic syndromes such as hyperlipidemia, hypercholesterolemia, hypertension, and type 2 diabetes. Approximately 20-30% of NAFLD cases progress to more severe chronic hepatitis, known as non-alcoholic steatohepatitis (NASH), showing deterioration of hepatic functions and liver fibrosis followed by cirrhosis and cancer. Previous studies uncovered that several metabolic regulators had roles in disease progression as key factors. Peroxisome proliferator-activated receptor alpha (PPARα) has been identified as one of the main players in hepatic lipid homeostasis. PPARα is abundantly expressed in hepatocytes, and is a ligand-dependent nuclear receptor belonging to the NR1C nuclear receptor subfamily, orchestrating lipid/glucose metabolism, inflammation, cell proliferation, and carcinogenesis. PPARα agonists are expected to be novel prescription drugs for NASH treatment, and some of them (e.g., Lanifibranor) are currently under clinical trials. These potential novel drugs are developed based on the knowledge of PPARα-activating target genes related to NAFLD and NASH. Intriguingly, PPARα is known to suppress the expression of subsets of target genes under agonist treatment; however, the mechanisms of PPARα-mediated gene suppression and functions of these genes are not well understood. In this review, we summarize and discuss the mechanisms of target gene repression by PPARα and the roles of repressed target genes on hepatic lipid metabolism, fibrosis and carcinogenesis related to NALFD and NASH, and provide future perspectives for PPARα pharmaceutical potentials.
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Affiliation(s)
- Tomoki Yagai
- Department of Metabolic Bioregulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
| | - Takahisa Nakamura
- Department of Metabolic Bioregulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.,Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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Tsai YT, Ruan JW, Chang CS, Ko ML, Chou HC, Lin CC, Lin CM, Huang CT, Wei YS, Liao EC, Chen HY, Lin LH, Lin MW, Kao CY, Chan HL. Proteomic and microbial assessments on the effect of Antrodia cinnamomea in C57BL/6 mice. Arch Biochem Biophys 2021; 713:109058. [PMID: 34627749 DOI: 10.1016/j.abb.2021.109058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 10/03/2021] [Accepted: 10/05/2021] [Indexed: 01/01/2023]
Abstract
Antrodia cinnamomea (AC) is a nutraceutical fungus and studies have suggested that AC has the potential to prevent or alleviate diseases. However, little is known about the AC-induced phenotypes on the intestine-liver axis and gut microbial alterations. Here, we performed two-dimensional difference gel electrophoresis (2D-DIGE) and MALDI-Biotyper to elaborate the AC-induced phenotypes on the intestine-liver axis and gut microbial distribution of C57BL/6 mice. The experimental outcomes showed that the hepatic density may increase by elevating hepatic redox regulation, lipid degradation and glycolysis-related proteins and alleviating cholesterol biosynthesis and transport-related proteins in C57BL/6 mice with AC treatment. Moreover, AC facilitates intestinal glycolysis, TCA cycle, redox and cytoskeleton regulation-related proteins, but also reduces intestinal vesicle transport-related proteins in C57BL/6 mice. However, the body weight, GTT, daily food/water intake, and fecal/urine weight were unaffected by AC supplementation in C57BL/6 mice. Notably, the C57BL/6-AC mice had a higher gut microbial abundance of Alistipes shahii (AS) than C57BL/6-Ctrl mice. In summary, the AC treatment affects intestinal permeability by regulating redox and cytoskeleton-related proteins and elevates the gut microbial abundance of AS in C57BL/6 mice that might be associated with increasing hepatic density and metabolism-related proteins of the liver in C57BL/6 mice. Our study provides an insight into the mechanisms of AC-induced phenotypes and a comprehensive assessment of AC's nutraceutical effect in C57BL/6 mice.
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Affiliation(s)
- Yi-Ting Tsai
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, 30013, Taiwan.
| | - Jhen-Wei Ruan
- Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan.
| | - Cherng-Shyang Chang
- Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli, 35053, Taiwan.
| | - Mei-Lan Ko
- Department of Ophthalmology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, 30059, Taiwan.
| | - Hsiu-Chuan Chou
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, 30013, Taiwan.
| | - Chi-Chien Lin
- Department of Life Sciences, Institute of Biomedical Science, National Chung Hsing University, Taichung, 402, Taiwan.
| | - Chiao-Mei Lin
- Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli, 35053, Taiwan.
| | - Chih-Ting Huang
- Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli, 35053, Taiwan.
| | - Yu-Shan Wei
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, 30013, Taiwan.
| | - En-Chi Liao
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, 30013, Taiwan.
| | - Hsin-Yi Chen
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, 30013, Taiwan.
| | - Li-Hsun Lin
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, 30013, Taiwan.
| | - Meng-Wei Lin
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, 30013, Taiwan.
| | - Cheng-Yuan Kao
- Immunology Research Center, National Health Research Institutes, Zhunan, Miaoli, 35053, Taiwan.
| | - Hong-Lin Chan
- Institute of Bioinformatics and Structural Biology and Department of Medical Sciences, National Tsing Hua University, Hsinchu, 30013, Taiwan.
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Tahri-Joutey M, Andreoletti P, Surapureddi S, Nasser B, Cherkaoui-Malki M, Latruffe N. Mechanisms Mediating the Regulation of Peroxisomal Fatty Acid Beta-Oxidation by PPARα. Int J Mol Sci 2021; 22:ijms22168969. [PMID: 34445672 PMCID: PMC8396561 DOI: 10.3390/ijms22168969] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/14/2021] [Accepted: 08/15/2021] [Indexed: 12/12/2022] Open
Abstract
In mammalian cells, two cellular organelles, mitochondria and peroxisomes, share the ability to degrade fatty acid chains. Although each organelle harbors its own fatty acid β-oxidation pathway, a distinct mitochondrial system feeds the oxidative phosphorylation pathway for ATP synthesis. At the same time, the peroxisomal β-oxidation pathway participates in cellular thermogenesis. A scientific milestone in 1965 helped discover the hepatomegaly effect in rat liver by clofibrate, subsequently identified as a peroxisome proliferator in rodents and an activator of the peroxisomal fatty acid β-oxidation pathway. These peroxisome proliferators were later identified as activating ligands of Peroxisome Proliferator-Activated Receptor α (PPARα), cloned in 1990. The ligand-activated heterodimer PPARα/RXRα recognizes a DNA sequence, called PPRE (Peroxisome Proliferator Response Element), corresponding to two half-consensus hexanucleotide motifs, AGGTCA, separated by one nucleotide. Accordingly, the assembled complex containing PPRE/PPARα/RXRα/ligands/Coregulators controls the expression of the genes involved in liver peroxisomal fatty acid β-oxidation. This review mobilizes a considerable number of findings that discuss miscellaneous axes, covering the detailed expression pattern of PPARα in species and tissues, the lessons from several PPARα KO mouse models and the modulation of PPARα function by dietary micronutrients.
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Affiliation(s)
- Mounia Tahri-Joutey
- Bio-PeroxIL Laboratory, University of Bourgogne Franche-Comté, 21000 Dijon, France; (M.T.-J.); (P.A.); (M.C.-M.)
- Laboratory of Biochemistry, Neurosciences, Natural Resources and Environment, Faculty of Sciences & Techniques, University Hassan I, BP 577, 26000 Settat, Morocco;
| | - Pierre Andreoletti
- Bio-PeroxIL Laboratory, University of Bourgogne Franche-Comté, 21000 Dijon, France; (M.T.-J.); (P.A.); (M.C.-M.)
| | - Sailesh Surapureddi
- Office of Pollution Prevention and Toxics, United States Environmental Protection Agency, Washington, DC 20460, USA;
| | - Boubker Nasser
- Laboratory of Biochemistry, Neurosciences, Natural Resources and Environment, Faculty of Sciences & Techniques, University Hassan I, BP 577, 26000 Settat, Morocco;
| | - Mustapha Cherkaoui-Malki
- Bio-PeroxIL Laboratory, University of Bourgogne Franche-Comté, 21000 Dijon, France; (M.T.-J.); (P.A.); (M.C.-M.)
| | - Norbert Latruffe
- Bio-PeroxIL Laboratory, University of Bourgogne Franche-Comté, 21000 Dijon, France; (M.T.-J.); (P.A.); (M.C.-M.)
- Correspondence:
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Xu Y, Xie L, Tang J, He X, Zhang Z, Chen Y, Zhou J, Gan B, Peng W. Morchella importuna Polysaccharides Alleviate Carbon Tetrachloride-Induced Hepatic Oxidative Injury in Mice. Front Physiol 2021; 12:669331. [PMID: 34413784 PMCID: PMC8369260 DOI: 10.3389/fphys.2021.669331] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 06/28/2021] [Indexed: 12/29/2022] Open
Abstract
This study aimed to investigate the effects of Morchella importuna polysaccharides (MIPs) on carbon tetrachloride (CCl4)-induced hepatic damage in mice. A total of 144 female mice were randomly assigned to four treatment groups, namely, control, CCl4, low-dose MIP (LMIP) group, and high-dose MIP (HMIP) group. After the 10-day experiment, serum and liver were sampled for biochemical and metabolomic analyses. The HMIPs markedly decreased the liver weight under CCl4 intoxication. Furthermore, the significantly elevated concentrations of five serum biochemical parameters, including alanine aminotransferase, aspartate aminotransferase, triglyceride, total cholesterol, and total bile acid under CCl4 treatment were subverted by MIP administration in a dose-dependent manner. Moreover, MIPs relieved the increased hepatic malonaldehyde and protein carbonyl content and the decreased superoxide dismutase and catalase contents caused by CCl4 intoxication. There was also a dose-dependent decrease in the CCl4-induced inflammatory indices, such as the levels of interleukin-1, interleukin-6, tumor necrosis factor-alpha, and myeloperoxidase, with MIP administration. Subsequent ultra-high performance liquid chromatography-tandem mass spectrometry-based serum metabolomics identified nine metabolites between the control and CCl4 groups and 10 metabolites between the HMIP and CCl4 groups, including some critical metabolites involved in flavonoid biosynthesis, amino acid metabolism, energy metabolism, and toxicant degradation. These novel findings indicate that MIPs may be of therapeutic value in alleviating the oxidative stress and inflammation caused by CCl4. Liquid chromatography-mass spectrometry-based metabolomics provides a valuable opportunity for identifying potential biomarkers and elucidating the protective mechanisms of medicinal mushrooms against hepatic oxidative injury.
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Affiliation(s)
- Yingyin Xu
- National-Local Joint Engineering Laboratory of Edible and Medicinal Fungi, Agricultural Resources and Environment Institute, Sichuan Academy of Agricultural Science, Chengdu, China
- Scientific Observing and Experimental Station of Agro-microbial Resource and Utilization in Southwest China, Ministry of Agriculture, Chengdu, China
| | - Liyuan Xie
- National-Local Joint Engineering Laboratory of Edible and Medicinal Fungi, Agricultural Resources and Environment Institute, Sichuan Academy of Agricultural Science, Chengdu, China
- Scientific Observing and Experimental Station of Agro-microbial Resource and Utilization in Southwest China, Ministry of Agriculture, Chengdu, China
| | - Jie Tang
- National-Local Joint Engineering Laboratory of Edible and Medicinal Fungi, Agricultural Resources and Environment Institute, Sichuan Academy of Agricultural Science, Chengdu, China
- Scientific Observing and Experimental Station of Agro-microbial Resource and Utilization in Southwest China, Ministry of Agriculture, Chengdu, China
| | - Xiaolan He
- National-Local Joint Engineering Laboratory of Edible and Medicinal Fungi, Agricultural Resources and Environment Institute, Sichuan Academy of Agricultural Science, Chengdu, China
- Scientific Observing and Experimental Station of Agro-microbial Resource and Utilization in Southwest China, Ministry of Agriculture, Chengdu, China
| | - Zhiyuan Zhang
- National-Local Joint Engineering Laboratory of Edible and Medicinal Fungi, Agricultural Resources and Environment Institute, Sichuan Academy of Agricultural Science, Chengdu, China
- Scientific Observing and Experimental Station of Agro-microbial Resource and Utilization in Southwest China, Ministry of Agriculture, Chengdu, China
| | - Ying Chen
- National-Local Joint Engineering Laboratory of Edible and Medicinal Fungi, Agricultural Resources and Environment Institute, Sichuan Academy of Agricultural Science, Chengdu, China
- Scientific Observing and Experimental Station of Agro-microbial Resource and Utilization in Southwest China, Ministry of Agriculture, Chengdu, China
| | - Jie Zhou
- National-Local Joint Engineering Laboratory of Edible and Medicinal Fungi, Agricultural Resources and Environment Institute, Sichuan Academy of Agricultural Science, Chengdu, China
- Scientific Observing and Experimental Station of Agro-microbial Resource and Utilization in Southwest China, Ministry of Agriculture, Chengdu, China
| | - Bingcheng Gan
- Institute of Urban Agriculture, Chinese Academy of Agricultural Sciences, Chengdu, China
| | - Weihong Peng
- National-Local Joint Engineering Laboratory of Edible and Medicinal Fungi, Agricultural Resources and Environment Institute, Sichuan Academy of Agricultural Science, Chengdu, China
- Scientific Observing and Experimental Station of Agro-microbial Resource and Utilization in Southwest China, Ministry of Agriculture, Chengdu, China
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Raza S, Tewari A, Rajak S, Sinha RA. Vitamins and non-alcoholic fatty liver disease: A Molecular Insight ⋆. LIVER RESEARCH (BEIJING, CHINA) 2021; 5:62-71. [PMID: 34221537 PMCID: PMC7611112 DOI: 10.1016/j.livres.2021.03.004] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 02/23/2021] [Accepted: 03/29/2021] [Indexed: 02/07/2023]
Abstract
The incidence of non-alcoholic fatty liver disease (NAFLD) is rising rapidly across the globe. NAFLD pathogenesis is largely driven by an imbalance in hepatic energy metabolism and at present, there is no approved drug for its treatment. The liver plays a crucial role in micronutrient metabolism and deregulation of this micronutrient metabolism may contribute to the pathogenesis of NAFLD. Vitamins regulate several enzymatic processes in the liver, and derangement in vitamin metabolism is believed to play a critical role in NAFLD progression. The anti-oxidant activities of vitamin C and E have been attributed to mitigate hepatocyte injury, and alterations in the serum levels of vitamin D, vitamin B12 and folate have shown a strong correlation with NAFLD severity. This review aims to highlight the role of these vitamins, which represent promising therapeutic targets for the management of NAFLD.
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Affiliation(s)
- Sana Raza
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Archana Tewari
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Sangam Rajak
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Rohit A. Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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32
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Rajak S, Iannucci LF, Zhou J, Anjum B, George N, Singh BK, Ghosh S, Yen PM, Sinha RA. Loss of ULK1 Attenuates Cholesterogenic Gene Expression in Mammalian Hepatic Cells. Front Cell Dev Biol 2020; 8:523550. [PMID: 33083385 PMCID: PMC7554540 DOI: 10.3389/fcell.2020.523550] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 09/11/2020] [Indexed: 12/18/2022] Open
Abstract
The hepatic mevalonate (MVA) pathway, responsible for cholesterol biosynthesis, is a therapeutically important metabolic pathway in clinical medicine. Using an unbiased transcriptomics approach, we uncover a novel role of Unc-51 like autophagy activating kinase 1 (ULK1) in regulating the expression of the hepatic de novo cholesterol biosynthesis/MVA pathway genes. Genetic silencing of ULK1 in non-starved mouse (AML-12) and human (HepG2) hepatic cells as well as in mouse liver followed by transcriptome and pathway analysis revealed that the loss of ULK1 expression led to significant down-regulation of genes involved in the MVA/cholesterol biosynthesis pathway. At a mechanistic level, loss of ULK1 led to decreased expression of SREBF2/SREBP2 (sterol regulatory element binding factor 2) via its effects on AKT-FOXO3a signaling and repression of SREBF2 target genes in the MVA pathway. Our findings, therefore, discover ULK1 as a novel regulator of cholesterol biosynthesis and a possible druggable target for controlling cholesterol-associated pathologies.
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Affiliation(s)
- Sangam Rajak
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Liliana F. Iannucci
- Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore
- Department of Biology, University of Padua, Padua, Italy
| | - Jin Zhou
- Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore
| | - B. Anjum
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Nelson George
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Brijesh K. Singh
- Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore
| | - Sujoy Ghosh
- Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore
| | - Paul M. Yen
- Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, Singapore
| | - Rohit A. Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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Fougerat A, Montagner A, Loiseau N, Guillou H, Wahli W. Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease. Cells 2020; 9:E1638. [PMID: 32650421 PMCID: PMC7408116 DOI: 10.3390/cells9071638] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/26/2020] [Accepted: 07/04/2020] [Indexed: 12/11/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate many functions that are disturbed in NAFLD, including glucose and lipid metabolism, as well as inflammation. Thus, they represent relevant clinical targets for NAFLD. In this review, we describe the determinants and mechanisms underlying the pathogenesis of NAFLD, its progression and complications, as well as the current therapeutic strategies that are employed. We also focus on the complementary and distinct roles of PPAR isotypes in many biological processes and on the effects of first-generation PPAR agonists. Finally, we review novel and safe PPAR agonists with improved efficacy and their potential use in the treatment of NAFLD.
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Affiliation(s)
- Anne Fougerat
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
| | - Alexandra Montagner
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
- Institut National de la Santé et de la Recherche Médicale (Inserm), Institute of Metabolic and Cardiovascular Diseases, UMR1048 Toulouse, France
- Institute of Metabolic and Cardiovascular Diseases, University of Toulouse, UMR1048 Toulouse, France
| | - Nicolas Loiseau
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
| | - Hervé Guillou
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
| | - Walter Wahli
- Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; (A.M.); (N.L.); (H.G.)
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Clinical Sciences Building, 11 Mandalay Road, Singapore 308232, Singapore
- Center for Integrative Genomics, Université de Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland
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Giammanco M, Di Liegro CM, Schiera G, Di Liegro I. Genomic and Non-Genomic Mechanisms of Action of Thyroid Hormones and Their Catabolite 3,5-Diiodo-L-Thyronine in Mammals. Int J Mol Sci 2020; 21:ijms21114140. [PMID: 32532017 PMCID: PMC7312989 DOI: 10.3390/ijms21114140] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/05/2020] [Accepted: 06/08/2020] [Indexed: 02/06/2023] Open
Abstract
Since the realization that the cellular homologs of a gene found in the retrovirus that contributes to erythroblastosis in birds (v-erbA), i.e. the proto-oncogene c-erbA encodes the nuclear receptors for thyroid hormones (THs), most of the interest for THs focalized on their ability to control gene transcription. It was found, indeed, that, by regulating gene expression in many tissues, these hormones could mediate critical events both in development and in adult organisms. Among their effects, much attention was given to their ability to increase energy expenditure, and they were early proposed as anti-obesity drugs. However, their clinical use has been strongly challenged by the concomitant onset of toxic effects, especially on the heart. Notably, it has been clearly demonstrated that, besides their direct action on transcription (genomic effects), THs also have non-genomic effects, mediated by cell membrane and/or mitochondrial binding sites, and sometimes triggered by their endogenous catabolites. Among these latter molecules, 3,5-diiodo-L-thyronine (3,5-T2) has been attracting increasing interest because some of its metabolic effects are similar to those induced by T3, but it seems to be safer. The main target of 3,5-T2 appears to be the mitochondria, and it has been hypothesized that, by acting mainly on mitochondrial function and oxidative stress, 3,5-T2 might prevent and revert tissue damages and hepatic steatosis induced by a hyper-lipid diet, while concomitantly reducing the circulating levels of low density lipoproteins (LDL) and triglycerides. Besides a summary concerning general metabolism of THs, as well as their genomic and non-genomic effects, herein we will discuss resistance to THs and the possible mechanisms of action of 3,5-T2, also in relation to its possible clinical use as a drug.
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Affiliation(s)
- Marco Giammanco
- Department of Surgical, Oncological and Oral Sciences (Discipline Chirurgiche, Oncologiche e Stomatologiche), University of Palermo, 90127 Palermo, Italy;
| | - Carlo Maria Di Liegro
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF)), University of Palermo, 90128 Palermo, Italy; (C.M.D.L.); (G.S.)
| | - Gabriella Schiera
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (Dipartimento di Scienze e Tecnologie Biologiche, Chimiche e Farmaceutiche (STEBICEF)), University of Palermo, 90128 Palermo, Italy; (C.M.D.L.); (G.S.)
| | - Italia Di Liegro
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (Dipartimento di Biomedicina, Neuroscienze e Diagnostica avanzata (Bi.N.D.)), University of Palermo, 90127 Palermo, Italy
- Correspondence: ; Tel.: +39-091-2389-7415 or +39-091-2389-7446
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