Abstract

Development of hepatic steatosis and its progression to steatohepatitis may be the consequence of dysfunction of several metabolic pathways, such as triglyceride synthesis, very low-density lipoprotein (VLDL) secretion, and fatty acid b-oxidation. Peroxisome proliferator- activated receptor c coactivator-1b (PGC-1b) is a master regulator of mitochondrial biogenesis and oxidative metabolism, lipogenesis, and triglyceride (TG) secretion. Here we generated a novel mouse model with constitutive hepatic activation of PGC-1b and studied the role of this transcriptional coactivator in dietary-induced steatosis and steatohepatitis. Selective activation of PGC-1b within hepatocytes is able to protect the liver from lipid overload and from progression to fibrosis. The protective function exerted by PGC-1b is due to its ability to induce mitochondrial oxidative phosphorylation, fatty acid b-oxidation, and citrate cycle, as well as to decrease oxidative stress and promote TG secretion in the blood stream. These findings bolster the concept that a combined hepatic specific action of PGC-1b on lipid synthesis and secretion, as well as on mitochondrial biogenesis and function, could protect against steatohepatitis. (HEPATOLOGY 2013;57:1343-1356)