Farnesoid X Receptor Agonists and Other Bile Acid Signaling Strategies for Treatment of Liver Disease

Abstract

The intracellular nuclear receptor farnesoid X receptor (FXR) and the transmembrane G protein-coupled receptor 5 (TGR5) respond to bile acids (BAs) by activating transcriptional networks and/or signaling cascades. These cascades affect the expression of a great number of target genes relevant for BA, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. FXR activation in the liver tissue and beyond, such as the gut-liver axis, kidney and adipose tissue, plays a role in metabolic diseases. These BA receptors activators hold promise to become a new class of drugs to be used in the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This review discusses the relevant BA receptors, the new drugs that target BA transport and signaling and their possible applications.

Origins of Portal Hypertension in Nonalcoholic Fatty Liver Disease

“…Finally, selective Experimental Intestinal decontamination by rifaximin blocks TLR4-mediated activation of HSCs and modulates FXR signaling by changing intestinal bile acid composition associated with reduced fibrosis, angiogenesis, and PVP in experimental PHT [69] beta3 receptor agonists induce relaxation of HSCs via cAMP accumulation and Rho-kinase inhibition with no effect on normal PVP, indicating that these drugs primarily target the dynamic components of IHVR [99,100]. FXR has recently become a major pharmacological target in NAFLD owing to its complex role in bile acid and lipid metabolism, inflammation, and fibrosis [101]. FXR increases the expression of dimethylarginine dimethylaminohydrolase (DDAH), which eliminates asymmetric dimethylarginine (ADMA), a competitive endogenous inhibitor of endothelial nitric oxide synthase (eNOS) abundant in cirrhosis [102].…”

Novel Targets and Drug Development in Portal Hypertension

“…It is a transcriptional regulator of bile acid homeostasis and highly expressed in the liver and small intestine [106]. Previous studies have demonstrated its role in inflammation, liver fibrosis, and vascular homeostasis [107,108]. Treatment with the selective semisynthetic FXR agonist obeticholic acid (OCA) reduced the hepatic resistance and portal pressure without systemic effects.…”

Nuclear receptors and liver disease: Summary of the 2017 basic research symposium

“…BA receptors FXR and G protein‐coupled bile acid receptor 5 (TGR5) regulate gene expression involved in the synthesis and transport of BAs and thus are major modulators of BA homeostasis and enterohepatic circulation 67. In addition, FXR has beneficial roles in triglyceride and cholesterol homeostasis and glucose metabolism 68.…”