GPR52 Accelerates Fatty Acid Biosynthesis in a Ligand-dependent Manner in Hepatocytes and in Response to Excessive Fat Intake in Mice

Overview

Journal iScience

Publisher Cell Press

Date 2021 Apr 2

PMID 33796846

Citations 1

Authors

Mitsuo Wada

Kayo Yukawa

Hiroyuki Ogasawara

Koichi Suzawa

Tatsuya Maekawa

Yoshihisa Yamamoto

Takeshi Ohta

Eunyoung Lee

Takashi Miki

Affiliations

Soon will be listed here.

Abstract

Gpr52 is an orphan G-protein-coupled receptor of unknown physiological function. We found that Gpr52-deficient ( ) mice exhibit leanness associated with reduced liver weight, decreased hepatic lipogenesis, and enhanced insulin sensitivity. Treatment of the hepatoma cell line HepG2 cells with c11, the synthetic GPR52 agonist, increased fatty acid biosynthesis, and GPR52 knockdown (KD) abolished the lipogenic action of c11. In addition, c11 induced the expressions of lipogenic enzymes ( and ), whereas these inductions were attenuated by GPR52-KD. In contrast, cholesterol biosynthesis was not increased by c11, but its basal level was significantly suppressed by GPR52-KD. High-fat diet (HFD)-induced increase in hepatic expression of and its targets ( and ) was absent in mice with alleviated hepatosteatosis. Our present study showed that hepatic GPR52 promotes the biosynthesis of fatty acid and cholesterol in a ligand-dependent and a constitutive manner, respectively, and Gpr52 participates in HFD-induced fatty acid synthesis in liver.

Citing Articles

Lecithin Inclusion by α-Cyclodextrin Activates SREBP2 Signaling in the Gut and Ameliorates Postprandial Hyperglycemia.

Lee E, Zhang X, Noda T, Miyamoto J, Kimura I, Tanaka T Int J Mol Sci. 2021; 22(19).

PMID: 34639136 PMC: 8509185. DOI: 10.3390/ijms221910796.

References

Luo J, Yang H, Song B . Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Biol. 2019; 21(4):225-245. DOI: 10.1038/s41580-019-0190-7. View

Sawzdargo M, Nguyen T, Lee D, Lynch K, Cheng R, Heng H . Identification and cloning of three novel human G protein-coupled receptor genes GPR52, PsiGPR53 and GPR55: GPR55 is extensively expressed in human brain. Brain Res Mol Brain Res. 1999; 64(2):193-8. DOI: 10.1016/s0169-328x(98)00277-0. View

Ntambi J, Miyazaki M, Stoehr J, Lan H, Kendziorski C, Yandell B . Loss of stearoyl-CoA desaturase-1 function protects mice against adiposity. Proc Natl Acad Sci U S A. 2002; 99(17):11482-6. PMC: 123282. DOI: 10.1073/pnas.132384699. View

Matsuzaka T, Shimano H, Yahagi N, Kato T, Atsumi A, Yamamoto T . Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance. Nat Med. 2007; 13(10):1193-202. DOI: 10.1038/nm1662. View

Kim C, Addy C, Kusunoki J, Anderson N, Deja S, Fu X . Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation. Cell Metab. 2017; 26(2):394-406.e6. PMC: 5603267. DOI: 10.1016/j.cmet.2017.07.009. View

Dobrzyn P, Jazurek M, Dobrzyn A . Stearoyl-CoA desaturase and insulin signaling--what is the molecular switch?. Biochim Biophys Acta. 2010; 1797(6-7):1189-94. DOI: 10.1016/j.bbabio.2010.02.007. View

Moran-Salvador E, Lopez-Parra M, Garcia-Alonso V, Titos E, Martinez-Clemente M, Gonzalez-Periz A . Role for PPARγ in obesity-induced hepatic steatosis as determined by hepatocyte- and macrophage-specific conditional knockouts. FASEB J. 2011; 25(8):2538-50. DOI: 10.1096/fj.10-173716. View

Guillou H, Zadravec D, Martin P, Jacobsson A . The key roles of elongases and desaturases in mammalian fatty acid metabolism: Insights from transgenic mice. Prog Lipid Res. 2009; 49(2):186-99. DOI: 10.1016/j.plipres.2009.12.002. View

Lin X, Li M, Wang N, Wu Y, Luo Z, Guo S . Structural basis of ligand recognition and self-activation of orphan GPR52. Nature. 2020; 579(7797):152-157. DOI: 10.1038/s41586-020-2019-0. View

10.

Mao J, DeMayo F, Li H, Abu-Elheiga L, Gu Z, Shaikenov T . Liver-specific deletion of acetyl-CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis. Proc Natl Acad Sci U S A. 2006; 103(22):8552-7. PMC: 1570106. DOI: 10.1073/pnas.0603115103. View

11.

Zhang Y, Hernandez-Ono A, Siri P, Weisberg S, Conlon D, Graham M . Aberrant hepatic expression of PPARgamma2 stimulates hepatic lipogenesis in a mouse model of obesity, insulin resistance, dyslipidemia, and hepatic steatosis. J Biol Chem. 2006; 281(49):37603-15. DOI: 10.1074/jbc.M604709200. View

12.

Yao Y, Cui X, Al-Ramahi I, Sun X, Li B, Hou J . A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity. Elife. 2015; 4. PMC: 4372774. DOI: 10.7554/eLife.05449. View

13.

Khan A, Agarwal H, Reddy S, Arige V, Natarajan B, Gupta V . MicroRNA 27a Is a Key Modulator of Cholesterol Biosynthesis. Mol Cell Biol. 2020; 40(9). PMC: 7156219. DOI: 10.1128/MCB.00470-19. View

14.

Chan M, Zhao Y, Heng C . Sequential responses to high-fat and high-calorie feeding in an obese mouse model. Obesity (Silver Spring). 2008; 16(5):972-8. DOI: 10.1038/oby.2008.32. View

15.

Abu-Elheiga L, Wu H, Gu Z, Bressler R, Wakil S . Acetyl-CoA carboxylase 2-/- mutant mice are protected against fatty liver under high-fat, high-carbohydrate dietary and de novo lipogenic conditions. J Biol Chem. 2012; 287(15):12578-88. PMC: 3321006. DOI: 10.1074/jbc.M111.309559. View

16.

Hatzipantelis C, Lu Y, Spark D, Langmead C, Stewart G . β-Arrestin-2-Dependent Mechanism of GPR52 Signaling in Frontal Cortical Neurons. ACS Chem Neurosci. 2020; 11(14):2077-2084. DOI: 10.1021/acschemneuro.0c00199. View

17.

Nishiyama K, Suzuki H, Maruyama M, Yoshihara T, Ohta H . Genetic deletion of GPR52 enhances the locomotor-stimulating effect of an adenosine A receptor antagonist in mice: A potential role of GPR52 in the function of striatopallidal neurons. Brain Res. 2017; 1670:24-31. DOI: 10.1016/j.brainres.2017.05.031. View

18.

Van den Boomen D, Volkmar N, Lehner P . Ubiquitin-mediated regulation of sterol homeostasis. Curr Opin Cell Biol. 2020; 65:103-111. DOI: 10.1016/j.ceb.2020.04.010. View

19.

Gusach A, Maslov I, Luginina A, Borshchevskiy V, Mishin A, Cherezov V . Beyond structure: emerging approaches to study GPCR dynamics. Curr Opin Struct Biol. 2020; 63:18-25. DOI: 10.1016/j.sbi.2020.03.004. View

20.

Mauvoisin D, Mounier C . Hormonal and nutritional regulation of SCD1 gene expression. Biochimie. 2010; 93(1):78-86. DOI: 10.1016/j.biochi.2010.08.001. View