Abstract
Peroxisome proliferator-activated receptors (PPARs) play major roles in the regulation of hepatic lipid metabolism through the control of numerous genes involved in processes such as lipid uptake and fatty acid oxidation. Here we identify hypoxia-inducible lipid droplet-associated (Hilpda/Hig2) as a novel PPAR target gene and demonstrate its involvement in hepatic lipid metabolism. Microarray analysis revealed that Hilpda is one of the most highly induced genes by the PPARα agonist Wy14643 in mouse precision cut liver slices. Induction of Hilpda mRNA by Wy14643 was confirmed in mouse and human hepatocytes. Oral dosing with Wy14643 similarly induced Hilpda mRNA levels in livers of wild-type mice but not Ppara(-/-) mice. Transactivation studies and chromatin immunoprecipitation showed that Hilpda is a direct PPARα target gene via a conserved PPAR response element located 1200 base pairs upstream of the transcription start site. Hepatic overexpression of HILPDA in mice via adeno-associated virus led to a 4-fold increase in liver triglyceride storage, without any changes in key genes involved in de novo lipogenesis, β-oxidation, or lipolysis. Moreover, intracellular lipase activity was not affected by HILPDA overexpression. Strikingly, HILPDA overexpression significantly impaired hepatic triglyceride secretion. Taken together, our data uncover HILPDA as a novel PPAR target that raises hepatic triglyceride storage via regulation of triglyceride secretion.
Highlights
Peroxisome proliferator-activated receptors (PPARs)␣ is an important regulator of hepatic lipid metabolism via target gene regulation
Hildpa Is Regulated by PPAR␣ in Liver Slices and Hepatocytes—To identify potential novel target genes of PPAR␣, mouse liver slices were treated with the PPAR␣ ligand Wy14643
2310016C08Rik/Hig2, later annotated as Hilpda, was of particular interest because it has recently been identified as a putative lipid droplet-associated protein that is regulated via a hypoxia-dependent mechanism involving HIF1 [23]
Summary
PPAR␣ is an important regulator of hepatic lipid metabolism via target gene regulation. Peroxisome proliferator-activated receptors (PPARs) play major roles in the regulation of hepatic lipid metabolism through the control of numerous genes involved in processes such as lipid uptake and fatty acid oxidation. Nuclear receptors comprise a family of transcription factors that bind to specific response elements across the genome and regulate the expression of a large network of genes [5] As a group, they are activated by a variety of steroid hormones and other lipid-derived compounds, including fat-soluble vitamins, cholesterol, and fatty acids [6]. Activation of PPAR␣ leads to induction of a large set of target genes involved in various pathways of lipid metabolism, including fatty acid transport, activation, storage, and oxidation [16, 17]. We identify Hilpda as a PPAR target in mouse and human hepatocytes and show that it plays an important role in hepatic triglyceride storage and secretion
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