Bile acid signaling in metabolic disease and drug therapy.
Animals; Bile Acids and Salts/biosynthesis/*metabolism/therapeutic use; Biological; Circadian Rhythm/physiology; G-Protein-Coupled/metabolism; Glucose/metabolism; Humans; Lipid Metabolism/physiology; Liver/metabolism; Metabolic Diseases/*drug therapy/*metabolism; Microbiota/physiology; MicroRNAs/metabolism; Models; Receptors; Signal Transduction/physiology
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid-activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein-coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver.
Li Tiangang; Chiang John Y L
Pharmacological reviews
2014
2014-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1124/pr.113.008201" target="_blank" rel="noreferrer noopener">10.1124/pr.113.008201</a>
Bile acid metabolism and signaling.
Animals; Bile Acids and Salts/*metabolism/therapeutic use; Biliary Tract Diseases/metabolism; Cholesterol/metabolism; Cytoplasmic and Nuclear/metabolism; Enterohepatic Circulation/physiology; Feedback; G-Protein-Coupled/metabolism; Homeostasis/physiology; Humans; Inflammation/metabolism; Liver/metabolism; Physiological/physiology; Receptors; Signal Transduction/*physiology
Bile acids are important physiological agents for intestinal nutrient absorption and biliary secretion of lipids, toxic metabolites, and xenobiotics. Bile acids also are signaling molecules and metabolic regulators that activate nuclear receptors and G protein-coupled receptor (GPCR) signaling to regulate hepatic lipid, glucose, and energy homeostasis and maintain metabolic homeostasis. Conversion of cholesterol to bile acids is critical for maintaining cholesterol homeostasis and preventing accumulation of cholesterol, triglycerides, and toxic metabolites, and injury in the liver and other organs. Enterohepatic circulation of bile acids from the liver to intestine and back to the liver plays a central role in nutrient absorption and distribution, and metabolic regulation and homeostasis. This physiological process is regulated by a complex membrane transport system in the liver and intestine regulated by nuclear receptors. Toxic bile acids may cause inflammation, apoptosis, and cell death. On the other hand, bile acid-activated nuclear and GPCR signaling protects against inflammation in liver, intestine, and macrophages. Disorders in bile acid metabolism cause cholestatic liver diseases, dyslipidemia, fatty liver diseases, cardiovascular diseases, and diabetes. Bile acids, bile acid derivatives, and bile acid sequestrants are therapeutic agents for treating chronic liver diseases, obesity, and diabetes in humans.
Chiang John Y L
Comprehensive Physiology
2013
2013-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/cphy.c120023" target="_blank" rel="noreferrer noopener">10.1002/cphy.c120023</a>