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Research ArticleCellular and Molecular

7α,25-Dihydroxycholesterol Suppresses Hepatocellular Steatosis through GPR183/EBI2 in Mouse and Human Hepatocytes

Jin Huang, Seung-Jin Lee, Saeromi Kang, Man Ho Choi and Dong-Soon Im
Journal of Pharmacology and Experimental Therapeutics July 2020, 374 (1) 142-150; DOI: https://doi.org/10.1124/jpet.120.264960
Jin Huang
College of Pharmacy, Pusan National University, Busan, Republic of Korea (J.H., S.-J.L., S.K., D.-S.I.); Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea (M.H.C.); and Laboratory of Pharmacology, College of Pharmacy, and Department of Life and Nanopharmaceutical Scicenses, Graduate School, Kyung Hee University, Seoul, Republic of Korea (D.-S.I.)
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Seung-Jin Lee
College of Pharmacy, Pusan National University, Busan, Republic of Korea (J.H., S.-J.L., S.K., D.-S.I.); Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea (M.H.C.); and Laboratory of Pharmacology, College of Pharmacy, and Department of Life and Nanopharmaceutical Scicenses, Graduate School, Kyung Hee University, Seoul, Republic of Korea (D.-S.I.)
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Saeromi Kang
College of Pharmacy, Pusan National University, Busan, Republic of Korea (J.H., S.-J.L., S.K., D.-S.I.); Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea (M.H.C.); and Laboratory of Pharmacology, College of Pharmacy, and Department of Life and Nanopharmaceutical Scicenses, Graduate School, Kyung Hee University, Seoul, Republic of Korea (D.-S.I.)
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Man Ho Choi
College of Pharmacy, Pusan National University, Busan, Republic of Korea (J.H., S.-J.L., S.K., D.-S.I.); Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea (M.H.C.); and Laboratory of Pharmacology, College of Pharmacy, and Department of Life and Nanopharmaceutical Scicenses, Graduate School, Kyung Hee University, Seoul, Republic of Korea (D.-S.I.)
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Dong-Soon Im
College of Pharmacy, Pusan National University, Busan, Republic of Korea (J.H., S.-J.L., S.K., D.-S.I.); Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea (M.H.C.); and Laboratory of Pharmacology, College of Pharmacy, and Department of Life and Nanopharmaceutical Scicenses, Graduate School, Kyung Hee University, Seoul, Republic of Korea (D.-S.I.)
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Abstract

Nonalcoholic fatty liver disease is a chronic inflammatory liver disease. It is associated with obesity and type 2 diabetes. Oxycholesterols are metabolites of cholesterol, and several of them can act on the G protein–coupled receptor, G protein–coupled receptor 183 (GPR183)/Epstein-Barr virus-induced gene 2. We found expression of GPR183 in human hepatoma cell lines and in vivo induction of GPR183 expression in mouse livers after high-fat diet feeding. Therefore, the role of oxycholesterols and GPR183 in hepatocytes was studied using a model of hepatic steatosis induced by liver X receptor (LXR) activation. LXR activation by T0901317 resulted in fat accumulation in Hep3B human hepatoma cells. This lipid accumulation was inhibited by 7α,25-dihydroxycholesterol, the most potent agonist of GPR183. The protective effects of 7α,25-dihydroxycholesterol were suppressed by a specific GPR183 antagonist, NIBR189 [(2E)-3-(4-Bromophenyl)-1-[4-4-methoxybenzoyl)-1-piperazinyl]-2-propene-1-one]. T0901317 treatment induced expression of the major transcription factor for lipogenesis, sterol regulatory element-binding protein 1c (SREBP-1c). 7α,25-Dihydroxycholesterol inhibited the induction of SREBP-1c proteins in a GPR183-dependent manner. Using inhibitors specific for intracellular signaling molecules, 7α,25-dihydroxycholesterol–induced suppression of hepatocellular steatosis was shown to be mediated through Gi/o proteins, p38 mitogen-activated protein kinases, phosphoinositide 3-kinase, and AMP-activated protein kinase. In addition, the inhibitory effect of 7α,25-dihydroxycholesterol was validated in HepG2 cells and primary mouse hepatocytes. Therefore, the present report suggests that 7α,25-dihydroxycholesterol–GPR183 signaling may suppress hepatocellular steatosis in the liver.

SIGNIFICANCE STATEMENT Oxycholesterols, which are metabolites of cholesterol, act on the G protein–coupled receptor, G protein–coupled receptor 183 (GPR183)/Epstein-Barr virus-induced gene 2, which is expressed in human hepatoma cell lines, and its expression is induced in vivo in mouse livers after high-fat diet feeding. Activation of GPR183 inhibits fat accumulation in primary mouse hepatocytes and HepG2 cells through Gi/o proteins, p38 mitogen-activated protein kinases, phosphoinositide 3-kinase, and AMP-activated protein kinase.

Footnotes

    • Received January 2, 2020.
    • Accepted October 4, 2020.
  • ↵1 Current affiliation: Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China

  • ↵2 J.H., S.-J.L., and S.K. contributed equally to this study.

  • This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology [2019R1D1A2C1005523].

  • Conflict of interest: The authors declare that there is no conflict of interest.

  • https://doi.org/10.1124/jpet.120.264960.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 374 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 374, Issue 1
1 Jul 2020
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Research ArticleCellular and Molecular

Oxysterol Protects Hepatic Steatosis via GPR183

Jin Huang, Seung-Jin Lee, Saeromi Kang, Man Ho Choi and Dong-Soon Im
Journal of Pharmacology and Experimental Therapeutics July 1, 2020, 374 (1) 142-150; DOI: https://doi.org/10.1124/jpet.120.264960

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Research ArticleCellular and Molecular

Oxysterol Protects Hepatic Steatosis via GPR183

Jin Huang, Seung-Jin Lee, Saeromi Kang, Man Ho Choi and Dong-Soon Im
Journal of Pharmacology and Experimental Therapeutics July 1, 2020, 374 (1) 142-150; DOI: https://doi.org/10.1124/jpet.120.264960
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