Bile acids: emerging role in management of liver diseases

Abstract

Bile acids are well known for their effects on cholesterol homeostasis and lipid digestion. Since the discovery of bile acid receptors, of which there are farnesoid X receptor (FXR), a nuclear receptor, and the plasma membrane G-protein receptor, as well as Takeda G-protein coupled receptor clone 5, further roles have been elucidated for bile acids including glucose and lipid metabolism as well as inflammation. Additionally, treatment with bile acid receptor agonists has shown a decrease in the amount of atherosclerosis plaque formation and decreased portal vascular resistance and portal hypotension in animal models. Furthermore, rodent models have demonstrated antifibrotic activity using bile acid receptor agonists. Early human data using a FXR agonist, obeticholic acid, have shown promising results with improvement of histological activity and even a reduction of fibrosis. Human studies are ongoing and will provide further information on bile acid receptor agonist therapies. Thus, bile acids and their derivatives have the potential for management of liver diseases and potentially other disease states including diabetes and the metabolic syndrome.

Keywords: Bile acids; FXR; Liver disease; TGR5.

Fig. 1

Schematic representation of the activation of TGR5 and FXR by bile acids. TGR5 is a plasma membrane G protein coupled receptor and FXR is a nuclear receptor that is activated by bile acids. The receptors are activated by both primary (CA and CDCA) and secondary bile acids (LCA and DCA). LCA is a potent activator of TGR5 while CDCA for FXR

Fig. 2

The Role of FXR on Lipid Metabolism and glucose homeostasis. FXR is activated by bile acids and has several downstream effects including inhibition of lipogenesis, decreased gluconeogenesis, increased insulin sensitivity and with recent data, a significant decrease in inflammation and fibrosis. FXR has the effect of increasing lipoprotein lipase by positively stimulating its activator, Apolipoprotein C2 (ApoC2), and repressing the inhibitor of lipoprotein lipase, Apolipoprotein C3 (ApoC3). The FLINT trial has shown an increase in Low-Density Lipoprotein (LDL) and a decrease in High-Density Lipoprotein (HDL)