Bile acid receptors and nonalcoholic fatty liver disease

Abstract

With the high prevalence of obesity, diabetes, and other features of the metabolic syndrome in United States, nonalcoholic fatty liver disease (NAFLD) has inevitably become a very prevalent chronic liver disease and is now emerging as one of the leading indications for liver transplantation. Insulin resistance and derangement of lipid metabolism, accompanied by activation of the pro-inflammatory response and fibrogenesis, are essential pathways in the development of the more clinically significant form of NAFLD, known as nonalcoholic steatohepatitis (NASH). Recent advances in the functional characterization of bile acid receptors, such as farnesoid X receptor (FXR) and transmembrane G protein-coupled receptor (TGR) 5, have provided further insight in the pathophysiology of NASH and have led to the development of potential therapeutic targets for NAFLD and NASH. Beyond maintaining bile acid metabolism, FXR and TGR5 also regulate lipid metabolism, maintain glucose homeostasis, increase energy expenditure, and ameliorate hepatic inflammation. These intriguing features have been exploited to develop bile acid analogues to target pathways in NAFLD and NASH pathogenesis. This review provides a brief overview of the pathogenesis of NAFLD and NASH, and then delves into the biological functions of bile acid receptors, particularly with respect to NASH pathogenesis, with a description of the associated experimental data, and, finally, we discuss the prospects of bile acid analogues in the treatment of NAFLD and NASH.

The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

“…NAFLD, however, can develop in patients with normal or lean body weight. NAFLD is defined by the presence of macrovesicular fat accumulation in more than 5% of hepatocytes in patients who consume less than 20 grams of alcohol per day (Yuan and Bambha, 2015). Alterations in lipid metabolism that ultimately lead to increased fat accumulation by hepatocytes lead to steatosis.…”

Bile acids and nonalcoholic fatty liver disease

“…The drug armamentarium to treat NAFLD/NASH is today rather limited, although new approaches are being intensively explored . In this context, bile acid (BA) derivatives and compounds that influence BA‐related signaling pathways are emerging as potentially useful therapeutic agents for NAFLD and NASH . In the present review, we provide a summary of current knowledge on the role of BAs in NAFLD/NASH and present new insights into the possible approach of targeting BA‐related pathways in the treatment of this serious global health problem.…”

Therapeutic modulation of the bile acid pool byCyp8b1knockdown protects against nonalcoholic fatty liver disease in mice

“…Moreover, BA receptors regulate the signaling pathways that are involved in myriad physiologic processes that are impaired in cardiometabolic disorders, such as lipid metabolism (18), glucose homeostasis (18,19), energy expenditure (20), and hepatic inflammation (21). In this context, BAs emerged as potential therapeutic targets for the treatment of NAFLD (16,22), and obeticholic acid (6ethyl-CDCA), a semisynthetic FXR agonist, is currently being investigated in a phase III trial in patients with NASH; however, use of FXR and TGR5 agonists has been restricted as a result of either a lack of efficacy or adverse effects (23,24). CYP8B1 is responsible for the overall hydrophobicity index of the BA pool, regardless of the secondary modifications of BAs that take place within the intestinal tract.…”