PMID- 35220131 OWN - NLM STAT- Publisher LR - 20231019 IS - 1618-095X (Electronic) IS - 0944-7113 (Linking) VI - 99 DP - 2022 May TI - 2,3,5,4'-tetrahydroxy-stilbene-2-O-beta-D-glucoside ameliorates NAFLD via attenuating hepatic steatosis through inhibiting mitochondrial dysfunction dependent on SIRT5. PG - 153994 LID - S0944-7113(22)00072-1 [pii] LID - 10.1016/j.phymed.2022.153994 [doi] AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming more and more common in clinic in the world, and the study on its mechanism and treatment strategy has already been a research hotspot. Natural chemical compound 2,3,5,4'-tetrahydroxy-stilbene-2-O-beta-d-glucoside (TSG) is isolated from Polygonum multiflorum Thunb. that has already been reported to have the lipid-lowering activity. PURPOSE: The purpose of this research was to observe the improvement of TSG on methionine and choline deficient (MCD) diet-induced NAFLD in mice and to further elucidate its engaged mechanism. METHODS: NAFLD was induced in mice fed by MCD diet for 6 weeks. The accumulation of lipids in hepatocytes was induced by 0.5 mM non-esterified fatty acid (NEFA). Biochemical parameters in serum or livers from mice were tested. Protein and mRNA expression and stability were measured. Mitochondrial dysfunction was analyzed both in vivo and in vitro. The Label-free quantitative proteomic analysis was used to find potential involved key molecules. RESULTS: TSG attenuated hepatic parenchymal cells injury, liver inflammatory responses and hepatic fibrosis, and markedly ameliorated liver steatosis in mice from MCD group. In vitro results indicated that TSG reduced the accumulation of cellular lipids in hepatocytes induced by NEFA. TSG reduced reactive oxygen species (ROS) formation and attenuated mitochondrial dysfunction both in vivo and in vitro. The label-free quantitative proteomic analysis predicted the crucial participation of NAD-dependent protein deacylase sirtuin-5 (SIRT5). Next experimental results further evidenced that TSG enhanced SIRT5 expression in mitochondria both in vitro and in vivo. The TSG-supplied inhibition on ROS formation and mitochondrial dysfunction in hepatocytes was disappeared after the application of SIRT5 siRNA. TSG increased the expression and enzymatic activity of carnitine palmitoyltransferase 1A (CPT1A), but this enhance was diminished in hepatocytes transfected with SIRT5 siRNA. Additionally, the TSG-provided inhibition on cellular lipids accumulation was also disappeared in hepatocytes transfected with SIRT5 siRNA. Further results demonstrated that TSG increased SIRT5 expression by regulating its mRNA stability through enhancing the binding of SIRT5 mRNA with serine/arginine-rich splicing factor 2 (SRSF2), which is an RNA-binding protein (RBP). CONCLUSION: TSG attenuated liver steatosis and inhibited NAFLD progression through preventing oxidative stress injury and improving mitochondrial dysfunction, and SIRT5 played a key role in this process. CI - Copyright (c) 2022. Published by Elsevier GmbH. FAU - Zhang, Shaobo AU - Zhang S AD - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. FAU - Wu, Zeqi AU - Wu Z AD - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. FAU - Shi, Liang AU - Shi L AD - Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric Research, Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, China. FAU - Yan, Shihao AU - Yan S AD - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. FAU - Huang, Zhenlin AU - Huang Z AD - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. FAU - Lu, Bin AU - Lu B AD - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. FAU - Wang, Zhengtao AU - Wang Z AD - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. FAU - Ji, Lili AU - Ji L AD - The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: lichenyue1307@126.com. LA - eng PT - Journal Article DEP - 20220214 PL - Germany TA - Phytomedicine JT - Phytomedicine : international journal of phytotherapy and phytopharmacology JID - 9438794 SB - IM OTO - NOTNLM OT - Mitochondrial dysfunction OT - NAFLD OT - Oxidative stress injury OT - SIRT5 OT - TSG EDAT- 2022/02/28 06:00 MHDA- 2022/02/28 06:00 CRDT- 2022/02/27 20:34 PHST- 2021/10/18 00:00 [received] PHST- 2022/01/17 00:00 [revised] PHST- 2022/02/13 00:00 [accepted] PHST- 2022/02/28 06:00 [pubmed] PHST- 2022/02/28 06:00 [medline] PHST- 2022/02/27 20:34 [entrez] AID - S0944-7113(22)00072-1 [pii] AID - 10.1016/j.phymed.2022.153994 [doi] PST - ppublish SO - Phytomedicine. 2022 May;99:153994. doi: 10.1016/j.phymed.2022.153994. Epub 2022 Feb 14.