Lack of GPR180 ameliorates hepatic lipid depot via downregulation of mTORC1 signaling.
Lack of GPR180 ameliorates hepatic lipid depot via downregulation of mTORC1 signaling.
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DOI：
10.1038/s41598-023-29135-5
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发表时间：
2023-02-01
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
我们之前在日本进行的全基因组关联研究探索了与瘦型非酒精性脂肪性肝病（NAFLD）相关的遗传位点，发现了四个候选位点，分别为chr6、chr7、chr12和chr13。本研究旨在确定在chr13中观察到的关联信号周围NAFLD的功能相关位点。染色体构象捕获分析和数据库调查表明，DNA片段在与相邻的四个编码基因启动子的关联信号中的分子间相互作用。用腺相关病毒载体（AAV8）传递的shRNA对小鼠进行KD敲低筛选，G蛋白偶联受体180 （Gpr180）的KD表现出改善肝脏脂质储存的作用。高脂饮食摄入后，Gpr180敲除（KO）小鼠的肝脏和血浆脂质水平也有所改善，但不影响糖代谢。转录组分析显示mTORC1信号和胆固醇稳态下调，这在Gpr180KO小鼠和人肝癌细胞系中通过mTOR磷酸化减弱和激活的SREBP1降低得到证实（Huh7）。aav8介导的GPR180表达在KO小鼠中的肝脏修复显示血浆和肝脏脂质水平的恢复。总之，消融GPR180可改善血浆和肝脏脂质水平，这是通过下调mTORC1信号通路介导的。
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.
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影响因子：
29
作者：
Yecies JL;Zhang HH;Menon S;Liu S;Yecies D;Lipovsky AI;Gorgun C;Kwiatkowski DJ;Hotamisligil GS;Lee CH;Manning BD
通讯作者：
Manning BD
影响因子：
4.5
作者：
Speliotes EK;Yerges-Armstrong LM;Wu J;Hernaez R;Kim LJ;Palmer CD;Gudnason V;Eiriksdottir G;Garcia ME;Launer LJ;Nalls MA;Clark JM;Mitchell BD;Shuldiner AR;Butler JL;Tomas M;Hoffmann U;Hwang SJ;Massaro JM;O'Donnell CJ;Sahani DV;Salomaa V;Schadt EE;Schwartz SM;Siscovick DS;NASH CRN;GIANT Consortium;MAGIC Investigators;Voight BF;Carr JJ;Feitosa MF;Harris TB;Fox CS;Smith AV;Kao WH;Hirschhorn JN;Borecki IB;GOLD Consortium
通讯作者：
GOLD Consortium
影响因子：
29.4
作者：
Cotter, Thomas G.;Rinella, Mary
通讯作者：
Rinella, Mary
影响因子：
37.8
作者：
Tsukada, S;Iwai, M;Tanaka, T
通讯作者：
Tanaka, T
东亚个体的关联分析和欧洲个体的跨血统分析揭示了与胆固醇和甘油三酯水平相关的新位点
影响因子：
3.5
作者：
Spracklen, Cassandra N.;Chen, Peng;Sim, Xueling
通讯作者：
Sim, Xueling