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Journal of Lipid Research, Vol. 50, 1621-1629, August 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Hepatic triacylglycerol hydrolysis regulates peroxisome proliferator-activated receptor activity

Jessica M. Sapiro^*, Mara T. Mashek^*, Andrew S. Greenberg and Douglas G. Mashek^1,*

^* Department of Food Science and Nutrition, University of Minnesota, St. Paul, MN 55108
Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111

¹ To whom correspondence should be addressed. e-mail: dmashek{at}umn.edu

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 (PPAR). 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 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 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 target genes were also decreased in response to ADRP overexpression. However, the PPAR ligand, WY-14643, was able to restore PPAR activity following ADRP overexpression. Despite its effects on PPAR, overexpressing ADRP did not affect PPAR activity. Enhancing TAG hydrolysis through ADRP knockdown or ATGL overexpression increased PPAR activity. These results indicate that TAG hydrolysis and the consequential release of fatty acids regulate PPAR activity.

Supplementary key words fatty acids • adipose differentiation-related protein • adipose triglyceride lipase

Abbreviations: Ad-GFP, adenovirus expressing green fluorescent protein; ADRP, adipose differentiation-related protein; AMPK, AMP-activated protein kinase; ATGL, adipose triacyglycerol lipase; EPA, eicosapentaenoic acid; HSL, hormone-sensitive lipase; PPAR, peroxisome proliferator-activated receptor; qRT-PCR, quantitative reverse transcription polymerase chain reaction; siRNA, short interfering RNA; TAG, triacylglycerol

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