SIRT1/PGC-1α signaling protects hepatocytes against mitochondrial oxidative stress induced by bile acids

Free Radical Research
M TanM Pan

Abstract

Oxidative stress and mitochondrial dysfunction are hypothesized to contribute to the pathogenesis of chronic cholestatic liver diseases. Silent information regulator 1 (SIRT1) attenuates oxidative stress and improves mitochondrial biogenesis in numerous mitochondrial-related diseases; however, a functional role for SIRT1 in chronic liver cholestasis, characterized by increased levels of toxic bile acids, remains unknown. We show decrease in SIRT1 levels and its activity and impairment of mitochondrial biogenesis in the liver of patients with extrahepatic cholestasis. Moreover, we found that glycochenodeoxycholic acid (GCDCA) stimulated cytotoxicity, disrupted the mitochondrial membrane potential, increased reactive oxygen species production, and decreased mitochondrial mass and mitochondrial DNA content in L02 cells. Consistent with this finding, GCDCA was found to decrease SIRT1 protein expression and activity, thus promoting the deacetylation of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α), a key enzyme involved in mitochondrial biogenesis and function. Conversely, GCDCA-induced mitochondrial injury was efficiently attenuated by SIRT1 overexpression. In summary, these findings indicate that t...Continue Reading

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Citations

Jul 1, 2017·Antioxidants & Redox Signaling·Nunzia D'OnofrioMaria Luisa Balestrieri
Jan 9, 2019·Molecular & Cellular Proteomics : MCP·Qi ZhaoFei Li
Jul 31, 2019·The Journal of Laryngology and Otology·H H R ChenD A Nunez
Jul 30, 2019·Oxidative Medicine and Cellular Longevity·Tingdong YanWeifeng Huang
Feb 28, 2020·Biomolecules·Miguel Fontecha-BarriusoAna Belen Sanz
Jul 13, 2016·Journal of Neuroscience Research·Bor Luen Tang
Jul 7, 2018·The American Journal of Chinese Medicine·Huan ZhangXiuli Men
Mar 21, 2020·Frontiers in Cardiovascular Medicine·Shafeeq A MohammedSarah Costantino
Sep 22, 2020·World Journal of Hepatology·Raquel T Yokoda, Eduardo A Rodriguez
Jan 25, 2020·Current Neuropharmacology·Huidan WengQinyong Ye
Mar 1, 2019·Molecular & Cellular Proteomics : MCP·Qi ZhaoFei Li

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