AG 1879 br Bile acids as therapeutic agents

Bile acids as therapeutic agents
Conclusion Bile acids are important physiological agents for nutrient AG 1879 and integrators of glucose, lipid, and energy metabolism control. Bile acid synthesis is tightly regulated to maintain metabolic homeostasis and prevent accumulation of highly toxic bile acids. Dysregulation of bile acid synthesis causes metabolic diseases, including cholestatic liver diseases, diabetes, and obesity. Activation of FXR and TGR5 by bile acids or their specific agonists improves insulin and glucose tolerance. These two bile acid receptors are critical for improving insulin sensitivity after vertical sleeve gastrectomy. Gastric bypass surgery in obese patients with diabetes rapidly improves insulin sensitivity and glycemic control before weight reduction and is associated with increased serum bile acids and GLP-1 levels. Activation of both FXR and TGR5 in the intestine may coordinately stimulate GLP-1 secretion to improve hepatic glucose and insulin sensitivity in diabetes. It is expected that FXR and TGR5 dual agonists will be developed as therapeutic agents for treatment of NAFLD and diabetes.
Conflict of interest
Acknowledgements This work was supported by US National Institutes of Health grants DK44442 and DK58379.
History of research into bile acids Historically, bile salts were thought to be (i) “detergent molecules” required for cholesterol solubilization in the gallbladder and (ii) stimulation for the absorption of lipids, cholesterol and fat-soluble vitamins from the intestines upon formation of mixed micelles. However, investigations into the role of bile acids were awakened in 1999 when three research teams reported that bile acids were natural ligands for the nuclear receptor (NR) farnesoid X receptor (FXR-α). FXR-α is highly expressed in the liver and gastrointestinal tract. Subsequent studies showed that FXR-α is a key regulator of the homeostasis of bile acids, glucose and lipids in the liver and intestines. In addition, FXR-α may play a crucial part in the pathophysiology of fatty liver, non-alcoholic steatohepatitis (NASH) and liver cancers. In 2003, the G protein-coupled receptor (GPCR) TGR5 was discovered and reported to be activated by bile acids in the order lithocholic acid (LCA) > deoxycholic acid (DCA) > chenodeoxycholic acid (CDCA) > cholic acid (CA) > ursodeoxycholic acid (UDCA). TGR5 is a Gαs-linked GPCR that activates the activity of adenylate cyclase, increases intracellular levels of cyclic adenosine monophosphate, and activates expression of protein kinase A. In the liver, TGR5 is expressed in macrophages, endothelial cells and cholangiocytes, but not in hepatocytes. In 2012, it was reported that conjugated bile acids (CBAs) activate another Gαi-linked GPCR, sphingosine-1-phosphate receptor 2 (S1PR2), in primary rodent hepatocytes and in vivo. S1PR2 is highly expressed in liver hepatocytes and cholangiocytes. CBAs are natural ligands of S1PR2, which rapidly activates the extracellular signal-regulated kinase (ERK)1/2 and AKT signaling pathways as well as nuclear sphingosine kinase 2 (SphK2) in hepatocytes. The physiologic and pathophysiologic importance of activation of specific NRs and GPCRs by different bile acids continues to be elucidated.
Enterohepatic circulation of bile acids during feeding The primary bile acids in humans, CA and CDCA, are synthesized from cholesterol by two biosynthetic pathways in liver hepatocytes. The “classic” or “neutral” pathway is the major pathway for the synthesis of bile acids in humans. This pathway is initiated by the rate-limiting enzyme cholesterol 7α-hydroxylase to synthesize the two primary bile acids CA and CDCA. The sterol 27α-hydroxylase is needed for the synthesis of CA in the classic pathway. The “acidic” or “alternative” pathway is initiated by mitochondrial sterol 27-hydroxylase, the activity of which is limited by the rate of transport of free cholesterol into the inner mitochondrial membrane. The acidic pathway generates mostly CDCA along with the oxysterols 25- and 27-hydroxycholesterol. Oxysterols are agonists for the liver X receptor, which is a key NR regulating the homeostasis of cholesterol within the cell. Once formed, bile acids are conjugated to glycine or taurine and secreted actively across the canalicular membrane of hepatocytes into bile by adenosine triphosphate-binding cassette (ABC) transporters (mainly ABCB11) along with phosphatidylcholine (by ABCB4) and free cholesterol (by ABCG5/ABCG8). These three major hepatic lipids form mixed micelles that are stored in the gallbladder.