Conversion of cholesterol to bile acids is the

Conversion of cholesterol to bile acids is the only significant catabolic pathway for elimination of excessive cholesterol in our body. Bile acids have long been recognized as important physiological agents that facilitate find out this here of dietary fats, steroids, drugs, and lipid soluble vitamins during the postprandial state. Bile acids are efficiently reabsorbed in the ileum and transported back to the liver via portal circulation. Enterohepatic circulation of bile acids not only exerts an important physiological function for transport of nutrients and drugs to the liver for metabolism and detoxification, but also plays a critical role in feedback inhibition of bile acid synthesis to reduce bile acid toxicity in the liver. Only the liver has the ability to synthesize bile acids from cholesterol. Bile acids control gut bacterial overgrowth and gut microbiota controls bile acid metabolism by converting primary bile acids to secondary bile acids. The liver to intestine axis regulates bile acid homeostasis and maintains hepatic metabolic homeostasis. Extensive basic research in bile acid metabolism over the past two decades has identified bile acids as signaling molecules that activate nuclear farnesoid X receptor (FXR) and membrane Gα-protein coupled bile acid receptor (Gpbar-1 or TGR5). These two bile acid receptors are expressed in the gastrointestinal track and play critical roles in the integrated regulation of glucose, lipid, and energy metabolism to maintain metabolic homeostasis in the liver. Alteration of bile acid metabolism and signaling contributes to the pathogenesis of liver-related diseases including cholestatic liver diseases, non-alcoholic fatty liver disease, diabetes, obesity, and liver cancer. Cholestatic liver diseases are chronic inflammatory liver diseases caused by obstruction or reduced bile flow out of the liver leading to accumulation of toxic bile acids in the liver. Nonalcoholic fatty liver disease (NAFLD) is manifested by accumulation of triglycerides in hepatocytes, and progresses to hepatic inflammation, fibrosis, and cirrhosis. NAFLD affects about 30% of the population worldwide. Some cirrhosis patients develop hepatocellular carcinoma (HCC), the second leading cause of liver cancer in the United States. Currently there is no effective drug therapy for treatment of cholestasis and NAFLD. Ursodeoxycholic acid (UDCA, Ursodiol) has been used for the treatment of cholesterol gallstone disease and primary biliary cirrhosis for many years with mixed results. Recent advances in bile acid research have successfully translated basic research to drug development by targeting FXR and TGR5 for cholestasis and NAFLD. Obeticholic acid (OCA, OCALIVA) is a semi-synthetic analogue of chenodeoxycholic acid and has been approved by the US Food and Drug Administration for treatment of primary biliary cirrhosis in 2016. A randomized global Phase 3 trial of OCA for non-alcoholic steatohepatitis is currently recruiting participants (NCT02548351, ). In this inaugural issue of , experts in bile acid research provide an up-to-date summary of bile acids in liver metabolism and diseases. The review “Bile acid metabolism and signaling in liver disease and therapy” by Chiang provides a general background on bile acid synthesis and regulation, the role of FXR and TGR5 signaling in metabolic liver diseases, and current bile acid-based drug therapies for liver diseases. The review “Bile acids as global regulators of hepatic nutrient metabolism” by Hylemon et al. describes the recently discovered conjugated-bile acid activated Gα-protein couple receptor, sphingosine-1-phosphate receptor 2 (S1PR2), in nutrient metabolism in hepatocytes. S1PR2 is activated by sphingosine-1-phosphate (S1P), which is synthesized from sphingosine by sphingosine kinases (SphKs). Interestingly, taurocholic acid has been shown to activate S1PR2 in hepatocytes. S1PR2 signals through extracellular regulated kinase ½ (ERK1/2), which is part of the mitogen-activated protein kinase (MAPK) pathway, and AKT (protein kinase B), which functions in insulin signaling. The physiological role and significance of S1PR2 signaling in hepatocytes is not clear.