Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic and cardiometabolic mortality. The rapidly increasing prevalence of this disease and of its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches to prevent disease progression to advanced fibrosis or cirrhosis and cancer. In recent years, bile acids have emerged as relevant signaling molecules that act at both hepatic and extrahepatic tissues to regulate lipid and carbohydrate metabolic pathways as well as energy homeostasis. Activation or modulation of bile acid receptors, such as the farnesoid X receptor and TGR5, and transporters, such as the ileal apical sodium-dependent bile acid transporter, appear to affect both insulin sensitivity and NAFLD/NASH pathogenesis at multiple levels, and these approaches hold promise as novel therapies. In the present review, we summarize current available data on the relationships of bile acids to NAFLD and the potential for therapeutically targeting bile-acid-related pathways to address this growing world-wide disease. (Hepatology 2017;65:350-362).

Figure 1

Schematic representation of the action of BAs as signaling molecules in several tissues: The nuclear receptor, FXR, is activated by BAs in the liver and has several downstream effects, including inhibition of lipogenesis, decreased BA synthesis, decreased gluconeogenesis, and increased insulin sensitivity. BAs also activate the Takeda G‐protein‐coupled receptor 5 (TGR5) in muscle and adipose tissues, increasing thermogenesis and energy expenditure. Also, activation of TGR5 in the intestine promotes GLP‐1 release from L cells, which, in turn, promotes insulin release from pancreatic β‐cells. In the terminal ileum, and after BA uptake by ASBT, FXR also stimulates production of FGF15 (mice) or 19 (human) that, upon binding to FGFR4 in liver cells, represses BA synthesis and promotes hepatic glycogen storage and FA oxidation. Abbreviation: TG, triglycerides.