The Bile Acid Receptor Tgr5 and High Fat, High Sugar‐Induced Liver Injury

Abstract

Background Progression of fatty liver disease to NASH/fibrosis is a major 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 G protein‐coupled bile acid receptor 1 (Gpbar1, aka Tgr5). Tgr5 is expressed in the gut and skeletal muscle, and in cholangiocytes and Kupffer cells of the liver. Activation of Tgr5 reduces inflammation through suppression of NFκB. Tgr5 also induces GLP‐1 secretion from enterocytes to improve insulin sensitivity. Here, we fed Tgr5‐/‐ mice a high fat, high fructose, and high sucrose diet to test the hypothesis that lack of Tgr5 would exacerbate the progression from fatty liver to NASH/fibrosis. Methods Female C57Bl/6J control wild type mice (WT) and Tgr5 knockout mice (Tgr5‐/‐) were fed a high fat (40% kcal), high fructose diet + 20% sucrose water (HFS) for 20 weeks. Metabolic phenotypes were characterized through examination of lipid and cholesterol metabolism pathways, and fibrosis and inflammation pathways. Results Tgr5‐/‐ mice fed HFS were more glucose intolerant compared to WT mice, despite gaining the same amount of weight. Tgr5‐/‐ mice fed HFS accumulated significantly more hepatic cholesterol and triglycerides compared to WT mice on the same diet, and gene expression of Acc and Fasn were significantly upregulated. Surprisingly, hepatic expression of genes involved in inflammation and fibrosis were significantly reduced in Tgr5‐/‐ mice fed HFS diet. Tgr‐/‐mice had significantly reduced expression of Col1a1, Col1a2, Tgfb, and Sma. Tgr5‐/‐ also had significantly reduced liver hydroxyproline, a measure of collagen production. Liver fibrosis is partly mediated through serotonin signaling. Tgr5‐/‐mice had significantly reduced expression of Maoa and the serotonin receptors Htr2a and Htr2b, which may have protected against the development of liver fibrosis in these mice. Conclusion Altered serotonin metabolism may protect Tgr5‐/‐ mice from the progression of steatosis to NASH/fibrosis induced by a high fat, high sugar diet.