Lack of GPR180 ameliorates hepatic lipid depot via downregulation of mTORC1 signaling
Abstract 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 N...
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| Format: | Article |
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Nature Portfolio
2023-02-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-29135-5 |
| _version_ | 1811171757415989248 |
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| author | Ken Yoshida Kazuha Yokota Kazuhisa Watanabe Hidetoshi Tsuda Ayumi Matsumoto Hiroaki Mizukami Sadahiko Iwamoto |
| author_facet | Ken Yoshida Kazuha Yokota Kazuhisa Watanabe Hidetoshi Tsuda Ayumi Matsumoto Hiroaki Mizukami Sadahiko Iwamoto |
| author_sort | Ken Yoshida |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-10T17:19:20Z |
| format | Article |
| id | doaj.art-594f6d5843124dcca237cbbd4eba4376 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-10T17:19:20Z |
| publishDate | 2023-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-594f6d5843124dcca237cbbd4eba43762023-02-05T12:10:51ZengNature PortfolioScientific Reports2045-23222023-02-0113111110.1038/s41598-023-29135-5Lack of GPR180 ameliorates hepatic lipid depot via downregulation of mTORC1 signalingKen Yoshida0Kazuha Yokota1Kazuhisa Watanabe2Hidetoshi Tsuda3Ayumi Matsumoto4Hiroaki Mizukami5Sadahiko Iwamoto6Division of Human Genetics, Center for Molecular Medicine, Jichi Medical UniversityDivision of Human Genetics, Center for Molecular Medicine, Jichi Medical UniversityDivision of Human Genetics, Center for Molecular Medicine, Jichi Medical UniversityDivision of Human Genetics, Center for Molecular Medicine, Jichi Medical UniversityDivision of Human Genetics, Center for Molecular Medicine, Jichi Medical UniversityDivision of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical SchoolDivision of Human Genetics, Center for Molecular Medicine, Jichi Medical UniversityAbstract 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.https://doi.org/10.1038/s41598-023-29135-5 |
| spellingShingle | Ken Yoshida Kazuha Yokota Kazuhisa Watanabe Hidetoshi Tsuda Ayumi Matsumoto Hiroaki Mizukami Sadahiko Iwamoto Lack of GPR180 ameliorates hepatic lipid depot via downregulation of mTORC1 signaling Scientific Reports |
| title | Lack of GPR180 ameliorates hepatic lipid depot via downregulation of mTORC1 signaling |
| title_full | Lack of GPR180 ameliorates hepatic lipid depot via downregulation of mTORC1 signaling |
| title_fullStr | Lack of GPR180 ameliorates hepatic lipid depot via downregulation of mTORC1 signaling |
| title_full_unstemmed | Lack of GPR180 ameliorates hepatic lipid depot via downregulation of mTORC1 signaling |
| title_short | Lack of GPR180 ameliorates hepatic lipid depot via downregulation of mTORC1 signaling |
| title_sort | lack of gpr180 ameliorates hepatic lipid depot via downregulation of mtorc1 signaling |
| url | https://doi.org/10.1038/s41598-023-29135-5 |
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