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Altered serotonin metabolism in Takeda G protein-coupled receptor 5 knockout mice protects against diet-induced hepatic fibrosis

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Liver Research 2022年第4期6卷 214-226页

作者： Jessica M.Ferrell Matthew Dilts Zachary Stahl Shannon Boehme Sabita Pokhrel Xinwen Wang John Y.L.Chiang Department of Integrative Medical Sciences Northeast Ohio Medical UniversityRootstownOHUSA Department of Pharmaceutical Sciences Northeast Ohio Medical UniversityRootstownOHUSA

Background and aims:Diet-induced obesity and metabolic syndrome can trigger the progression of fatty liver disease to non-alcoholic steatohepatitis and fibrosis,which is a major public health *** acids regulate metabolic homeostasis and inflammation in the liver and gut via the activation of nuclear farnesoid X receptor(Fxr)and the membrane receptor Takeda G protein-coupled receptor 5(Tgr5).Tgr5 is highly expressed in the gut and skeletal muscle,and in cholangiocytes and Kupffer cells of the ***5 is implicated in the mediation of liver and gut inflammation,as well as the maintenance of energy ***,we used a high fat,high fructose,and high sucrose(HFS)diet to determine how bile acid signaling through Tgr5 may regulate metabolism during the progression from fatty liver to non-alcoholic steatohepatitis and *** and methods:Female C57BL/6J control wild type(WT)and Tgr5 knockout(Tgr5^(-/-))mice were fed HFS(high fat(40%kcal),high fructose,and 20%sucrose water)diet for 20 *** phe-notypes were characterized through examination of bile acid synthesis pathways,lipid and cholesterol metabolism pathways,and fibrosis and inflammation ***:Tgr5^(-/-)mice were more glucose intolerant when fed HFS diet,despite gaining the same amount of weight as WT ***5^(-/-)mice accumulated significantly more hepatic cholesterol and triglycerides on HFS diet compared to WT mice,and gene expression of lipogenic genes was significantly *** cholesterol 7alpha-hydroxylase(Cyp7a1)gene expression was consistently elevated in Tgr5^(-/-)mice,while oxysterol 7alpha-hydroxylase(Cyp7b1),sterol 27-hydroxylase(Cyp27a1),Fxr,and small heterodimer partner(Shp)were downregulated by HFS ***,hepatic inflammation and fibrosis were also significantly reduced in Tgr5^(-/-)mice fed HFS diet,which may be due to altered se-rotonin signaling in the ***:Tgr5^(-/-)mice may be protected from high fat,high sugar-

关键词： Non-alcoholic fatty liver disease(NAFLD) Liver fibrosis Takeda G protein-coupled receptor 5(TGR5) Serotonin(5-HT) high fat,high fructose,and high sucrose (HFS)

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