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Perilipin 5 is a novel target of nuclear receptor LRH-1 to regulate hepatic triglycerides metabolism
Rubee Pantha1 (Graduate Student), Jae-Ho Lee1 (Research worker), Jae-Hoon Bae1 (Professor), Eun Hee Koh2 (Professor), Minsang Shin3 (Professor), Dae-Kyu Song1 (Professor), Seung-Soon Im 1,* (Professor)
1Physiology, Keimyung University School of Medicine, Daegu 42601, Republic of Korea,
2Internal Medicine, University of Ulsan College of Medicine, Seoul, 05505 Republic of Korea,
3Microbiology, School of Medicine, Kyungpook National University, 680 Gukchaebosang-Ro, Jung-gu, Daegu, 41944, South Korea
Abstract
Liver receptor homolog-1 (LRH-1) has emerged as a regulator of hepatic glucose, bile acid, and mitochondrial metabolism. However, the functional mechanism underlying the effect of LRH-1 on lipid mobilization has not been addressed. This study investigated the regulatory function of LRH-1 in lipid metabolism in maintaining a normal liver physiological state during fasting. The Lrh-1f/f and LRH-1 liver-specific knockout (Lrh-1LKO) mice were either fed or fasted for 24 h, and the liver and serum were isolated. The livers were used for qPCR, western blot, and histological analysis. Primary hepatocytes were isolated for immunocytochemistry assessments of lipids. During fasting, the Lrh-1LKO mice showed increased accumulation of triglycerides in the liver compared to that in Lrh-1f/f mice. Interestingly, in the Lrh-1LKO liver, decreases in perilipin 5 (PLIN5) expression and genes involved in モ-oxidation were observed. In addition, the LRH-1 agonist dialauroylphosphatidylcholine also enhanced PLIN5 expression in human cultured HepG2 cells. To identify new target genes of LRH-1, these findings directed us to analyze the PLIN5 promoter sequence, which revealed −1620/−1614 to be a putative binding site for LRH-1. This was confirmed by promoter activity and chromatin immuno-precipitation assays. Additionally, fasted Lrh-1f/f primary hepatocytes showed 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 a novel target of LRH-1 to mobilize LDs, protect the liver from lipid overload, and manage the cellular needs during fasting.
Abstract, Accepted Manuscript(in press) [Submitted on April 20, 2021, Accepted on August 9, 2021]
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