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.