PMID- 36566874
OWN - NLM
STAT- MEDLINE
DCOM- 20230120
LR  - 20230224
IS  - 1879-2618 (Electronic)
IS  - 1388-1981 (Linking)
VI  - 1868
IP  - 3
DP  - 2023 Mar
TI  - Enzymatically-epoxidized docosahexaenoic acid, 19,20-EpDPE, suppresses hepatic 
      crown-like structure formation and nonalcoholic steatohepatitis fibrosis through 
      GPR120.
PG  - 159275
LID - S1388-1981(22)00165-2 [pii]
LID - 10.1016/j.bbalip.2022.159275 [doi]
AB  - 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.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Aoki, Hidenori
AU  - Aoki H
AD  - 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.
FAU - Isobe, Yosuke
AU  - Isobe Y
AD  - 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.
FAU - Yoshida, Mio
AU  - Yoshida M
AD  - 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.
FAU - Kang, Jing X
AU  - Kang JX
AD  - Laboratory for Lipid Medicine and Technology, Massachusetts General Hospital and 
      Harvard Medical School, 02114 Boston, MA, USA.
FAU - Maekawa, Masashi
AU  - Maekawa M
AD  - 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.
FAU - Arita, Makoto
AU  - Arita M
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221222
PL  - Netherlands
TA  - Biochim Biophys Acta Mol Cell Biol Lipids
JT  - Biochimica et biophysica acta. Molecular and cell biology of lipids
JID - 101731727
RN  - 25167-62-8 (Docosahexaenoic Acids)
RN  - 0 (Fatty Acids, Omega-3)
RN  - 0 (Receptors, G-Protein-Coupled)
SB  - IM
MH  - Mice
MH  - Animals
MH  - *Non-alcoholic Fatty Liver Disease/drug therapy/metabolism
MH  - Docosahexaenoic Acids/pharmacology
MH  - Disease Models, Animal
MH  - Fibrosis
MH  - Liver Cirrhosis/drug therapy
MH  - *Fatty Acids, Omega-3/metabolism
MH  - Receptors, G-Protein-Coupled/genetics
OTO - NOTNLM
OT  - 19,20-EpDPE
OT  - Cyp4f18
OT  - GPR120
OT  - Hepatic crown like structure
OT  - Liver fibrosis
OT  - NASH
COIS- Declaration of competing interest We declare that they have no known competing 
      financial interests or personal relationships that could have appeared to 
      influence the work reported in this paper.
EDAT- 2022/12/26 06:00
MHDA- 2023/01/21 06:00
CRDT- 2022/12/25 19:13
PHST- 2022/08/15 00:00 [received]
PHST- 2022/12/13 00:00 [revised]
PHST- 2022/12/14 00:00 [accepted]
PHST- 2022/12/26 06:00 [pubmed]
PHST- 2023/01/21 06:00 [medline]
PHST- 2022/12/25 19:13 [entrez]
AID - S1388-1981(22)00165-2 [pii]
AID - 10.1016/j.bbalip.2022.159275 [doi]
PST - ppublish
SO  - Biochim Biophys Acta Mol Cell Biol Lipids. 2023 Mar;1868(3):159275. doi: 
      10.1016/j.bbalip.2022.159275. Epub 2022 Dec 22.