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Bile Acid Membrane Receptor TGR5 Inhibits Alcohol‐Induced Liver Steatosis
Author(s) -
Fan Mingjie,
Liu Yanjun,
Tu Jui,
Wang Yangmeng,
Jin Lihua,
Huang Wendong
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04972
Subject(s) - g protein coupled bile acid receptor , steatosis , bile acid , alcoholic liver disease , steatohepatitis , cirrhosis , fatty liver , medicine , endocrinology , liver injury , liver disease , chemistry , biology , disease
Alcoholic liver disease (ALD) is one of the leading causes of liver failure in the world. It progresses from alcoholic fatty liver (AFL) to alcoholic steatohepatitis (ASH), which is characterized with hepatic inflammation. Chronic ASH will result in fibrosis, cirrhosis and hepatocellular cancer (HCC) eventually. However, very few treatment options for ALD are available currently. Therefore, there is an urgent unmet medical need to better understand the molecular mechanisms underneath the development of ALD and develop effective treatment approaches. Bile acid signaling in the liver‐gastrointestinal tract axis is important for the integrated regulation of lipid, glucose, and energy metabolism. Dysregulated bile acid signaling is associated with ALD due to the fact that alcohol significantly alters bile acids pool and composition in humans and rodents. G‐protein‐coupled bile acid receptor, Gpbar1 (TGR5), is a membrane bound bile acid receptor. It is more broadly expressed, but its hepatic expression is limited to Kupffer cells, macrophages and sinusoidal endothelial cells. Little information regarding the effects of TGR5 in the pathological development of ALD has been reported before. In this study, we use C57BL/6(WT) and TGR5 knockout ( TGR5 − / − ) mice to study the potential role of TGR5 in alcohol‐induced liver disease. Mice were challenged with chronic 5% ethanol feeding (10 days) plus a binge dose of alcohol by oral gavage (5 g/kg body weight) or with acute high dose alcohol gavage. The results showed that the liver/body weight ratio was increased in both WT and TGR5 − / − ethanol fed mice, while it was significant higher in ethanol fed TGR5 − / − mice than WT mice. The liver injury marker serum alanine transaminase (ALT) and aspartate aminotransferase (AST) were both increased. Alcohol feeding altered gene expression in bile acid homeostasis. The hepatic triglycerides were upregulated almost 30% higher in TGR5 − / − mice than WT group. The haematoxylin Eosin (H&E) and Oil Red O staining showed more fat vacuoles in the liver of ethanol fed TGR5 − / − mice than that in WT mice. We also treat the mice with a novel potent TGR5 agonist ligand and found protective effects on ALD in WT but not TGR5 − / − mice. Collectively, these results suggest that TGR5 may prevent the development of ALD and represent a novel target for ALD treatment. Support or Funding Information City of Hope Departmental Internal funding