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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Perilipin 5 is a novel target of nuclear receptor LRH-1 to regulate hepatic triglycerides metabolism

  • Pantha, Rubee (Department of Physiology, Keimyung University School of Medicine) ;
  • Lee, Jae-Ho (Department of Physiology, Keimyung University School of Medicine) ;
  • Bae, Jae-Hoon (Department of Physiology, Keimyung University School of Medicine) ;
  • Koh, Eun Hee (Department of Internal Medicine, Asan Institute for Life Science, University of Ulsan College of Medicine) ;
  • Shin, Minsang (Department of Microbiology, School of Medicine, Kyungpook National University) ;
  • Song, Dae-Kyu (Department of Physiology, Keimyung University School of Medicine) ;
  • Im, Seung-Soon (Department of Physiology, Keimyung University School of Medicine)
  • Received : 2021.04.20
  • Accepted : 2021.08.09
  • Published : 2021.09.30
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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 β-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 immunoprecipitation 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.

Keywords

Acknowledgement

We acknowledge Dr. Timothy F. Osborne at Johns Hopkins University School of Medicine for kindly providing Lrh-1f/f mice. This study was supported by grants of the Korea Research Foundation, an NRF grant funded by the Korea Government (MSIP) (2019R1A2C2085302, NRF-2021R1A4A1029238) and KMPC (2013M3A9D5072550).

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