Enzymatically-epoxidized docosahexaenoic acid, 19,20-EpDPE, suppresses hepatic crown-like structure formation and nonalcoholic steatohepatitis fibrosis through GPR120

Hidenori Aoki; Yosuke Isobe; Mio Yoshida; Jing X Kang; Masashi Maekawa; Makoto Arita

doi:10.1016/j.bbalip.2022.159275

Enzymatically-epoxidized docosahexaenoic acid, 19,20-EpDPE, suppresses hepatic crown-like structure formation and nonalcoholic steatohepatitis fibrosis through GPR120

Biochim Biophys Acta Mol Cell Biol Lipids. 2023 Mar;1868(3):159275. doi: 10.1016/j.bbalip.2022.159275. Epub 2022 Dec 22.

Authors

Hidenori Aoki¹, Yosuke Isobe¹, Mio Yoshida¹, Jing X Kang², Masashi Maekawa¹, Makoto Arita³

Affiliations

¹ Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan; Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa 230-0045, Japan.
² Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital and Harvard Medical School, 02114 Boston, MA, USA.
³ Division of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan; Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa 230-0045, Japan; Cellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, Kanagawa 230-0045, Japan. Electronic address: arita-mk@pha.keio.ac.jp.

PMID: 36566874
DOI: 10.1016/j.bbalip.2022.159275

Abstract

A hepatic crown-like structure (hCLS) formed by macrophages accumulating around lipid droplets and dead cells in the liver is a unique feature of nonalcoholic steatohepatitis (NASH) that triggers progression of liver fibrosis. As hCLS plays a key role in the progression of NASH fibrosis, hCLS formation has emerged as a potential therapeutic target. n-3 polyunsaturated fatty acids (n-3 PUFAs) have potential suppressive effects on NASH fibrosis; however, the mechanisms underlying this effect are poorly understood. Here, we report that n-3 PUFA-enriched Fat-1 transgenic mice are resistant to hCLS formation and liver fibrosis in a NASH model induced by a combination of high-fat diet, CCl4 and a Liver X receptor (LXR) agonist. Liquid chromatography-tandem mass spectrometry-based mediator lipidomics revealed that the amount of endogenous n-3 PUFA-derived metabolites, such as 17,18-dihydroxyeicosatetraenoic acid (17,18-diHETE), and 19,20-epoxy docosapentaenoic acid (19,20-EpDPE), was significantly elevated in Fat-1 mice, along with hCLS formation. In particular, DHA-derived 19,20-EpDPE produced by Cyp4f18 attenuated the hCLS formation and liver fibrosis in a G protein-coupled receptor 120 (GPR120)-dependent manner. These results indicated that 19,20-EpDPE is an endogenous active metabolite that mediates the preventive effect of n-3 PUFAs against NASH fibrosis.

Keywords: 19,20-EpDPE; Cyp4f18; GPR120; Hepatic crown like structure; Liver fibrosis; NASH.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Disease Models, Animal
Docosahexaenoic Acids / pharmacology
Fatty Acids, Omega-3* / metabolism
Fibrosis
Liver Cirrhosis / drug therapy
Mice
Non-alcoholic Fatty Liver Disease* / drug therapy
Non-alcoholic Fatty Liver Disease* / metabolism
Receptors, G-Protein-Coupled / genetics

Substances

Docosahexaenoic Acids
Fatty Acids, Omega-3
Receptors, G-Protein-Coupled