Altered serotonin metabolism in Takeda G protein-coupled receptor 5 knockout mice protects against diet-induced hepatic fibrosis
Title
Altered serotonin metabolism in Takeda G protein-coupled receptor 5 knockout mice protects against diet-induced hepatic fibrosis
Creator
Ferrell, Jessica M
Dilts, Matthew
Stahl, Zachary
Boehme, Shannon
Pokhrel, Sabita
Wang, Xinwen
Chiang, John Y.L.
Date
2022
Description
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 concern. Bile 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 liver. Tgr5 is implicated in the mediation of liver and gut inflammation, as well as the maintenance of energy homeostasis. Here, 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 fibrosis.
Results Tgr5−/− mice were more glucose intolerant when fed HFS diet, despite gaining the same amount of weight as WT mice. Tgr5−/− mice accumulated significantly more hepatic cholesterol and triglycerides on HFS diet compared to WT mice, and gene expression of lipogenic genes was significantly upregulated. Hepatic 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 diet. Surprisingly, hepatic inflammation and fibrosis were also significantly reduced in Tgr5−/− mice fed HFS diet, which may be due to altered serotonin signaling in the liver.
Conclusions Tgr5−/− mice may be protected from high fat, high sugar-induced hepatic inflammation and injury due to altered serotonin metabolism.
Results Tgr5−/− mice were more glucose intolerant when fed HFS diet, despite gaining the same amount of weight as WT mice. Tgr5−/− mice accumulated significantly more hepatic cholesterol and triglycerides on HFS diet compared to WT mice, and gene expression of lipogenic genes was significantly upregulated. Hepatic 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 diet. Surprisingly, hepatic inflammation and fibrosis were also significantly reduced in Tgr5−/− mice fed HFS diet, which may be due to altered serotonin signaling in the liver.
Conclusions Tgr5−/− mice may be protected from high fat, high sugar-induced hepatic inflammation and injury due to altered serotonin metabolism.
Source
In Liver Research December 2022 6(4):214-226
Language
English
Citation
Ferrell, Jessica M et al., “Altered serotonin metabolism in Takeda G protein-coupled receptor 5 knockout mice protects against diet-induced hepatic fibrosis,” NEOMED Bibliography Database, accessed April 26, 2024, https://neomed.omeka.net/items/show/12213.