title: SIRT1/PGC-1α signaling protects hepatocytes against mitochondrial oxidative stress induced by bile acids.
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 the loss of SIRT1 may play a crucial role in the pathogenesis of liver damage observed in patients with extrahepatic cholestasis. The findings also indicate that genetic supplementation of SIRT1 can ameliorate GCDCA-induced hepatotoxicity through the activation of PGC-1α-dependent mitochondrial biogenesis.
authors: Second Department of Hepatobiliary Surgery, Zhujiang Hospital, State Key Laboratory of Organ Failure Research, Co-Innovation Center for Organ Failure Research, Southern Medical University , Guangzhou , P. R. China.
authors: M
authors: M
authors: Tan
authors: C
authors: C
authors: Tang
authors: Y
authors: Y
authors: Zhang
authors: Y
authors: Y
authors: Cheng
authors: L
authors: L
authors: Cai
authors: X
authors: X
authors: Chen
authors: Y
authors: Y
authors: Gao
authors: Y
authors: Y
authors: Deng
authors: M
authors: M
authors: Pan
mesh_terms: D000107:Acetylation; D000328:Adult; D001647:Bile Acids and Salts / Q000502:physiology*; D002460:Cell Line; D001651:Cholestasis, Extrahepatic / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D001678:Organelle Biogenesis; D018384:Oxidative Stress; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011499:Protein Processing, Post-Translational; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D001647:Bile Acids and Salts; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: GCDCA; PGC-1α; SIRT1; hepatotoxicity; mitochondrial biogenesis