PGC-1α overexpression results in increased hepatic fatty acid oxidation with reduced triacylglycerol accumulation and secretion

Morris EM, Meers GM, Booth FW, Fritsche KL, Hardin CD, Thyfault JP, Ibdah JA. PGC-1 alpha overexpression results in increased hepatic fatty acid oxidation with reduced triacylglycerol accumulation and secretion. Am J Physiol Gastrointest Liver Physiol 303: G979-G992, 2012. First published August 16, 2012; doi: 10.1152/ajpgi.00169.2012.-Studies have shown that decreased mitochondrial content and function are associated with hepatic steatosis. We examined whether peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) overexpression and a subsequent increase in mitochondrial content and function in rat primary hepatocytes (in vitro) and Sprague-Dawley rats (in vivo) would comprehensively alter mitochondrial lipid metabolism, including complete (CO2) and incomplete (acid-soluble metabolites) fatty acid oxidation (FAO), tricarboxylic acid cycle flux, and triacylglycerol (TAG) storage and export. PGC-1 alpha overexpression in primary hepatocytes produced an increase in markers of mitochondrial content and function (citrate synthase, mitochondrial DNA, and electron transport system complex proteins) and an increase in FAO, which was accompanied by reduced TAG storage and TAG secretion compared with control. Also, the PGC-1 alpha-overexpressing hepatocytes were protected from excess TAG accumulation following overnight lipid treatment. PGC-1 alpha overexpression in hepatocytes lowered expression of genes critical to VLDL assembly and secretion (apolipoprotein B and microsomal triglyceride transfer protein). Adenoviral transduction of rats with PGC-1 alpha resulted in a liver-specific increase in PGC-1 alpha expression and produced an in vivo liver phenotype of increased FAO via increased mitochondrial function that also resulted in reduced hepatic TAG storage and decreased plasma TAG levels. In conclusion, overexpression of hepatic PGC-1 alpha and subsequent increases in FAO through elevated mitochondrial content and/or function result in reduced TAG storage and secretion in the in vitro and in vivo milieu.