Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease

Abstract

Dyslipidemia is an important risk factor for cardiovascular disease (CVD) and atherosclerosis. When dyslipidemia coincides with other metabolic disorders such as obesity, hypertension, and glucose intolerance, defined as the metabolic syndrome (MS), individuals present an elevated risk to develop type 2 diabetes (T2D) as well as CVD. Because the MS epidemic represents a growing public health problem worldwide, the development of therapies remains a major challenge. Alterations of bile acid pool regulation in T2D have revealed a link between bile acid and metabolic homeostasis. The bile acid receptors farnesoid X receptor (FXR) and TGR5 both regulate lipid, glucose, and energy metabolism, rendering them potential pharmacological targets for MS therapy. This review discusses the mechanisms of metabolic regulation by FXR and TGR5 and the utility relevance of natural and synthetic modulators of FXR and TGR5 activity, including bile acid sequestrants, in the treatment of the MS.

Fig. 1.

Functions of FXR and TGR5 in metabolic homeostasis and effect of bile acid receptor modulation. See text for details. The indication of agonist or BAS effects was omitted in case of contradictory data in the literature. Functions of FXR, black on white; functions of TGR5, white on black; functions of both receptors, white on gray. Blue flash, effect of receptor activation; red flash, effect of bile acid sequestration. SM, skeletal muscle; WAT, white adipose tissue.