Abstract
Peroxisome proliferator-activated receptor delta (PPARD) is a transcription factor regulating many important genes involved in lipid and glucose metabolism. Hepatic lysophosphatidylcholine acyltransferase 3 (LPCAT3) plays critical functions in TG secretion and ER stress response due to its unique ability to catalyze the incorporation of polyunsaturated fatty acids into phospholipids. Previous studies identified liver X receptor as the transcription factor controlling LPCAT3 expression in liver tissue. Here we showed for the first time that the hepatic LPCAT3 gene is transcriptionally regulated by PPARD in vitro and in vivo . Treatments of HepG2, Huh-7, and Hepa 1-6 cells with PPARD specific agonists (L-165041 and GW0742) increased LPCAT3 mRNA levels 2-3 fold of control. Adenovirus-mediated knockdown of PPARD in HepG2 cells reduced the basal level of LPCAT3 mRNA by approximately 40% compared to control and further attenuated the induction of PPARD agonist on LPCAT3 gene expression. To demonstrate the direct regulation of PPARD on LPCAT3 gene transcription, we analyzed human LPCAT3 promoter sequence and identified two putative PPAR responsive elements (PPRE-1, -171; PPRE-2, -727) within 1 kb of the proximal LPCAT3 promoter. LPCAT3 promoter assays demonstrated strong inductions of the reporter activity by PPARD agonists. Mutational analysis of the human LPCAT3 promoter revealed that the PPRE-1 is involved in conferring responsiveness to PPARD agonist mediated transcriptional activity. Direct binding of PPARD to PPRE-1 sequence was demonstrated by chromatin immunoprecipitation and gel retardation assays. Finally, we provided in vivo evidence showing that activation of PPARD by L-165041 in mice increased LPCAT3 mRNA abundance in the liver. Altogether, these new findings identify LPCAT3 as a direct PPARD target gene and suggest a novel function of PPARD in regulation of phospholipid metabolism through LPCAT3.
Published Version
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