Abstract
Regulation of hepatic gene expression by dietary fatty acids is primarilymediatedbyproxisomeproliferator activated receptor alpha (PPAR ). While the role of PPAR in mouse liver has been extensively studied, much less is known about its function in human liver. We used human primary hepatocytes whichwere isolated from 6 individual donors, including both male and female and ranging in age from 44 to 73 years. The cells were treated with PPAR agonist Wy14643 (50 M) for 6 and 24h. Gene expression profiles were assessed by using human genome U133 Plus 2.0 arrays. We observed that up to 204–174 genes (6 and 24h time point, respectively) were changed using a cutoff of P<0.05 and mean fold change ≥1.1. Significantly regulated genes were further analyzed using ingenuity pathway analyzer, which revealed fatty acid metabolism as the most regulated metabolic pathway. Therefore, we zoomed in to categorize the lipid metabolism connected genes based on their cellular localization and related lipidmetabolic process within the hepatocyte. A large number of genes implicated in lipid metabolism were found to be regulated by PPAR in primary human hepatocytes. This included classical PPAR targets involved in mitochondrial fatty acid oxidation, fatty acid binding and activation, glycerol metabolism, lipid transporting, and fatty acid desaturation. In addition, novel putative targets of PPAR were identified which are involved in lipid metabolism. Overall, we can conclude that the detailed functions of PPAR in lipid metabolism are extremely well conserved between mouse and human.
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