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.
Highlights
Dyslipidemia is an important risk factor for cardiovascular disease (CVD) and atherosclerosis
This review focuses on recent advances in the understanding of bile acids (BA) metabolism and the function of farnesoid X receptor (FXR) and TGR5 in lipid, glucose, and energy metabolism as well as in atherosclerosis
HDL-C levels decrease whereas LDL-C levels increase (Intercept Pharmaceuticals press release 01/10/2009; communication at the European Association for the Study of Diabetes 2009), confirming that FXR activation may be beneficial to lower plasma TG but not cholesterol, similar to chenodeoxycholic acid (CDCA) [36, 105]
Summary
BA are amphipatic molecules and major constituents of bile. Their synthesis from cholesterol in the hepatocyte represents an important way to eliminate cholesterol from the human body. Once excreted into the small intestine, primary BA are deconjugated and partially converted into secondary BA by dehydroxylation [9] These modifications are catalyzed by enzymes of the microbial flora, which in turn are regulated by BA [10]. In addition to inhibiting the expression of their transepithelial transporters apical sodium/bile acid cotransporter (ASBT) and organic solute transporter (OST)␣/ in the intestine [12], they are strong transcriptional inhibitors of CYP7A1, exerting a negative feedback regulation of their own synthesis [6]. These regulatory functions of BA are mediated by signaling through their receptors, FXR
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