Hepatic triacylglycerol hydrolysis regulates peroxisome proliferator-activated receptor α activity

Recent evidence suggests that fatty acids generated from intracellular triacylglycerol (TAG) hydrolysis may have important roles in intracellular signaling. This study was conducted to determine if fatty acids liberated from TAG hydrolysis regulate peroxisome proliferator-activated receptor alpha (PPAR alpha). Primary rat hepatocyte cultures were treated with adenoviruses overexpressing adipose differentiation-related protein (ADRP) or adipose triacylglycerol lipase (ATGL) or treated with short interfering RNA (siRNA) targeted against ADRP. Subsequent effects on TAG metabolism and PPAR alpha activity and target gene expression were determined. Overexpressing ADRP attenuated TAG hydrolysis, whereas siRNA-mediated knockdown of ADRP or ATGL overexpression resulted in enhanced TAG hydrolysis. Results from PPAR alpha reporter activity assays demonstrated that decreasing TAG hydrolysis by ADRP overexpression resulted in a 35-60% reduction in reporter activity under basal conditions or in the presence of fatty acids. As expected, PPAR alpha target genes were also decreased in response to ADRP overexpression. However, the PPAR alpha ligand, WY-14643, was able to restore PPAR alpha activity following ADRP overexpression. Despite its effects on PPAR alpha, overexpressing ADRP did not affect PPAR gamma activity. Enhancing TAG hydrolysis through ADRP knockdown or ATGL overexpression increased PPAR alpha activity. These results indicate that TAG hydrolysis and the consequential release of fatty acids regulate PPAR alpha activity.-Sapiro, J. M., M. T. Mashek, A. S. Greenberg, and D. G. Mashek. Hepatic triacylglycerol hydrolysis regulates peroxisome proliferator-activated receptor alpha activity. J. Lipid Res. 2009. 50: 1621-1629.