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A more recent version of this article appeared on February 1, 2006

Papers In Press, published online ahead of print November 10, 2005
J. Lipid Res., doi:10.1194/jlr.M500203-JLR200
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Submitted on May 19, 2005
Revised on November 10, 2005
Accepted on November 10, 2005

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

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

Molecular Pharmacology, AstraZeneca R&D Mölndal, Mölndal S-431 83

Corresponding Author: 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 PPARalpha agonist Wy14,643 (Wy), the 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, while the apoB secretion increased. Thus, decreased availability of triglycerides for VLDL assembly could help to explain the cellular accumulation of triglycerides following Wy treatment. We hypothesized that this effect could be mediated by increased ADRP expression. Similar to PPARalpha activation, adenovirus mediated ADRP overexpression in mouse hepatocytes enhanced cellular triglyceride mass and decreased 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 due to decreased cellular triglycerides following increased fatty acid oxidation since the triglyceride mass in Wy treated ADRP overexpressing cells was unchanged. In summary, PPARalpha activation prevents availability of triglycerides for VLDL assembly and increases hepatic triglyceride content in part by increasing the expression of ADRP.


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