PMID- 36726016
OWN - NLM
STAT- MEDLINE
DCOM- 20230206
LR  - 20230316
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 13
IP  - 1
DP  - 2023 Feb 1
TI  - Lack of GPR180 ameliorates hepatic lipid depot via downregulation of mTORC1 
      signaling.
PG  - 1843
LID - 10.1038/s41598-023-29135-5 [doi]
LID - 1843
AB  - Our previous genome-wide association study to explore genetic loci associated 
      with lean nonalcoholic fatty liver disease (NAFLD) in Japan suggested four 
      candidate loci, which were mapped to chr6, chr7, chr12 and chr13. The present 
      study aimed to identify the locus involved functionally in NAFLD around the 
      association signal observed in chr13. Chromosome conformation capture assay and a 
      database survey suggested the intermolecular interaction among DNA fragments in 
      association signals with the adjacent four coding gene promoters. The four genes 
      were further screened by knockdown (KD) in mice using shRNA delivered by an 
      adeno-associated virus vector (AAV8), and KD of G protein-coupled receptor 180 
      (Gpr180) showed amelioration of hepatic lipid storage. Gpr180 knockout (KO) mice 
      also showed ameliorated hepatic and plasma lipid levels without influencing 
      glucose metabolism after high-fat diet intake. Transcriptome analyses showed 
      downregulation of mTORC1 signaling and cholesterol homeostasis, which was 
      confirmed by weakened phosphorylation of mTOR and decreased activated SREBP1 in 
      Gpr180KO mice and a human hepatoma cell line (Huh7). AAV8-mediated hepatic rescue 
      of GPR180 expression in KO mice showed recovery of plasma and hepatic lipid 
      levels. In conclusion, ablation of GPR180 ameliorated plasma and hepatic lipid 
      levels, which was mediated by downregulation of mTORC1 signaling.
CI  - (c) 2023. The Author(s).
FAU - Yoshida, Ken
AU  - Yoshida K
AD  - Division of Human Genetics, Center for Molecular Medicine, Jichi Medical 
      University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
FAU - Yokota, Kazuha
AU  - Yokota K
AD  - Division of Human Genetics, Center for Molecular Medicine, Jichi Medical 
      University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
FAU - Watanabe, Kazuhisa
AU  - Watanabe K
AD  - Division of Human Genetics, Center for Molecular Medicine, Jichi Medical 
      University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
FAU - Tsuda, Hidetoshi
AU  - Tsuda H
AD  - Division of Human Genetics, Center for Molecular Medicine, Jichi Medical 
      University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
FAU - Matsumoto, Ayumi
AU  - Matsumoto A
AD  - Division of Human Genetics, Center for Molecular Medicine, Jichi Medical 
      University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.
FAU - Mizukami, Hiroaki
AU  - Mizukami H
AD  - Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical 
      School, Tochigi, Japan.
FAU - Iwamoto, Sadahiko
AU  - Iwamoto S
AD  - Division of Human Genetics, Center for Molecular Medicine, Jichi Medical 
      University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan. 
      siwamoto@jichi.ac.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230201
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Lipids)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (GPR180 protein, human)
SB  - IM
MH  - Animals
MH  - Humans
MH  - Mice
MH  - Diet, High-Fat/adverse effects
MH  - Down-Regulation
MH  - Genome-Wide Association Study
MH  - Lipid Metabolism
MH  - Lipids
MH  - Liver/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - Mice, Inbred C57BL
MH  - *Non-alcoholic Fatty Liver Disease/genetics/metabolism
MH  - *Receptors, G-Protein-Coupled/genetics/metabolism
PMC - PMC9892563
COIS- The authors declare no competing interests.
EDAT- 2023/02/03 06:00
MHDA- 2023/02/04 06:00
PMCR- 2023/02/01
CRDT- 2023/02/02 00:01
PHST- 2022/08/09 00:00 [received]
PHST- 2023/01/31 00:00 [accepted]
PHST- 2023/02/02 00:01 [entrez]
PHST- 2023/02/03 06:00 [pubmed]
PHST- 2023/02/04 06:00 [medline]
PHST- 2023/02/01 00:00 [pmc-release]
AID - 10.1038/s41598-023-29135-5 [pii]
AID - 29135 [pii]
AID - 10.1038/s41598-023-29135-5 [doi]
PST - epublish
SO  - Sci Rep. 2023 Feb 1;13(1):1843. doi: 10.1038/s41598-023-29135-5.