Perilipin 5 is a novel target of nuclear receptor LRH-1 to regulate hepatic triglycerides metabolism
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Liver receptor homolog-1 (LRH-1) has emerged as a regulatorof hepatic glucose, bile acid, and mitochondrial metabolism. However, the functional mechanism underlying the effect ofLRH-1 on lipid mobilization has not been addressed. Thisstudy investigated the regulatory function of LRH-1 in lipidmetabolism in maintaining a normal liver physiological stateduring fasting. The Lrh-1f/f and LRH-1 liver-specific knockout(Lrh-1LKO) mice were either fed or fasted for 24 h, and the liverand serum were isolated. The livers were used for qPCR,western blot, and histological analysis. Primary hepatocyteswere isolated for immunocytochemistry assessments of lipids. During fasting, the Lrh-1LKO mice showed increased accumulationof triglycerides in the liver compared to that in Lrh-1f/fmice. Interestingly, in the Lrh-1LKO liver, decreases in perilipin5 (PLIN5) expression and genes involved in β-oxidation wereobserved. In addition, the LRH-1 agonist dialauroylphosphatidylcholinealso enhanced PLIN5 expression in human culturedHepG2 cells. To identify new target genes of LRH-1, these findingsdirected us to analyze the Plin5 promoter sequence, whichrevealed −1620/−1614 to be a putative binding site for LRH-1. This was confirmed by promoter activity and chromatin immunoprecipitationassays. Additionally, fasted Lrh-1f/f primary hepatocytesshowed increased co-localization of PLIN5 in lipid droplets(LDs) compared to that in fasted Lrh-1LKO primary hepatocytes. Overall, these findings suggest that PLIN5 might be anovel target of LRH-1 to mobilize LDs, protect the liver fromlipid overload, and manage the cellular needs during fasting.
Abstract
Liver receptor homolog-1 (LRH-1) has emerged as a regulatorof hepatic glucose, bile acid, and mitochondrial metabolism. However, the functional mechanism underlying the effect ofLRH-1 on lipid mobilization has not been addressed. Thisstudy investigated the regulatory function of LRH-1 in lipidmetabolism in maintaining a normal liver physiological stateduring fasting. The Lrh-1f/f and LRH-1 liver-specific knockout(Lrh-1LKO) mice were either fed or fasted for 24 h, and the liverand serum were isolated. The livers were used for qPCR,western blot, and histological analysis. Primary hepatocyteswere isolated for immunocytochemistry assessments of lipids. During fasting, the Lrh-1LKO mice showed increased accumulationof triglycerides in the liver compared to that in Lrh-1f/fmice. Interestingly, in the Lrh-1LKO liver, decreases in perilipin5 (PLIN5) expression and genes involved in β-oxidation wereobserved. In addition, the LRH-1 agonist dialauroylphosphatidylcholinealso enhanced PLIN5 expression in human culturedHepG2 cells. To identify new target genes of LRH-1, these findingsdirected us to analyze the Plin5 promoter sequence, whichrevealed −1620/−1614 to be a putative binding site for LRH-1. This was confirmed by promoter activity and chromatin immunoprecipitationassays. Additionally, fasted Lrh-1f/f primary hepatocytesshowed increased co-localization of PLIN5 in lipid droplets(LDs) compared to that in fasted Lrh-1LKO primary hepatocytes. Overall, these findings suggest that PLIN5 might be anovel target of LRH-1 to mobilize LDs, protect the liver fromlipid overload, and manage the cellular needs during fasting.
참고문헌 (32)
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