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Journal of Lipid Research, Vol. 47, 329-340, February 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

PPAR activation increases triglyceride mass and adipose differentiation-related protein in hepatocytes

Ulrika Edvardsson^1,*,,, Anna Ljungberg^*,, Daniel Lindén^*,, Lena William-Olsson, Helena Peilot-Sjögren, Andrea Ahnmark and Jan Oscarsson^*,,

^* Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg, Sweden
Department of Physiology, Sahlgrenska University Hospital, Göteborg, Sweden
AstraZeneca Research and Development, Mölndal, Sweden

Published, JLR Papers in Press, November 10, 2005.

¹ To whom correspondence should be addressed. e-mail: ulrika.edvardsson{at}astrazeneca.com

Adipose differentiation-related protein (ADRP) is a lipid droplet-associated protein that is expressed in various tissues. In mice treated with the peroxisome proliferator-activated receptor (PPAR) agonist Wy14,643 (Wy), hepatic mRNA and protein levels of ADRP as well as hepatic triglyceride content increased. Also in primary mouse hepatocytes, Wy increased ADRP expression and intracellular triglyceride mass. The triglyceride mass increased in spite of unchanged triglyceride biosynthesis and increased palmitic acid oxidation. However, Wy incubation decreased the secretion of newly synthesized triglycerides, whereas apolipoprotein B secretion increased. Thus, decreased availability of triglycerides for VLDL assembly could help to explain the cellular accumulation of triglycerides after Wy treatment. We hypothesized that this effect could be mediated by increased ADRP expression. Similar to PPAR activation, adenovirus-mediated ADRP overexpression in mouse hepatocytes enhanced cellular triglyceride mass and decreased the secretion of newly synthesized triglycerides. In ADRP-overexpressing cells, Wy incubation resulted in a further decrease in triglyceride secretion. This effect of Wy was not attributable to decreased cellular triglycerides after increased fatty acid oxidation because the triglyceride mass in Wy-treated ADRP-overexpressing cells was unchanged. In summary, PPAR activation prevents the availability of triglycerides for VLDL assembly and increases hepatic triglyceride content in part by increasing the expression of ADRP.

Supplementary key words Wy14,643 • primary hepatocytes • triglyceride synthesis • fatty acid oxidation • triglyceride secretion • apolipoprotein B-100 • apolipoprotein B-48 • peroxisome proliferator-activated receptor

Abbreviations: ADRP, adipose differentiation-related protein; apoB, apolipoprotein B; DGAT, diacylglycerol acyltransferase; MTP, microsomal triglyceride transfer protein; PPAR, peroxisome proliferator-activated receptor ; PPRE, peroxisome proliferator-activated receptor response element; Wy, Wy14,643; 36B4, acidic ribosomal phosphoprotein P0

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