The Role of Bile Acids in Cardiovascular Diseases: from Mechanisms to Clinical Implications

Abstract

Bile acids (BAs), key regulators in the metabolic network, are not only involved in lipid digestion and absorption but also serve as potential therapeutic targets for metabolic disorders. Studies have shown that cardiac dysfunction is associated with abnormal BA metabolic pathways. As ligands for several nuclear receptors and membrane receptors, BAs systematically regulate the homeostasis of metabolism and participate in cardiovascular diseases (CVDs), such as myocardial infarction, diabetic cardiomyopathy, atherosclerosis, arrhythmia, and heart failure. However, the molecular mechanism by which BAs trigger CVDs remains controversial. Therefore, the regulation of BA signal transduction by modulating the synthesis and composition of BAs is an interesting and novel direction for potential therapies for CVDs. Here, we mainly summarized the metabolism of BAs and their role in cardiomyocytes and noncardiomyocytes in CVDs. Moreover, we comprehensively discussed the clinical prospects of BAs in CVDs and analyzed the clinical diagnostic and application value of BAs. The latest development prospects of BAs in the field of new drug development are also prospected. We aimed to elucidate the underlying mechanism of BAs treatment in CVDs, and the relationship between BAs and CVDs may provide new avenues for the prevention and treatment of these diseases.

Keywords: Bile acids; cardiomyocytes; cardiovascular diseases; metabolism; noncardiomyocytes.

Figure 1.

Synthesis and metabolism of BAs. There are two pathways to synthesize BAs, namely, the classical pathway and the alternative pathway[12]. The formation process includes multiple reaction steps. In the classical pathway, cholesterol is catalyzed by cholesterol-7α-hydroxylase (CYP7A1) to first generate 7α-hydroxycholesterol as an intermediate product, which is further catalyzed to generate CA and CDCA. The BA alternative pathway is theoretically present in the mitochondria of all cells or tissues. In this pathway, cholesterol is first catalyzed by sterol-27-hydroxylase (CYP27A1) to generate the intermediate product 27-hydroxycholesterol, which is then hydrogenated by sterol-7α-hydroxylase (CYP7B1) to form CDCA. The alternative approach mainly produces CDCA.

Figure 2.

BAs affect cardiovascular disease by binding to various receptors that affect metabolism and regulation of lipid profiles. These receptors include nuclear receptors (FXR, PXR, VDR, LXR), G protein-coupled receptor (TGR5, muscarinic receptor, S1PR) and Ca²⁺-activated potassium (K+) (BK) channels. These receptors are highly expressed in cells associated with the cardiovascular system, such as cardiomyocytes, endothelial cells, cardiac fibroblasts and vascular smooth muscle cells. By binding to receptors on cells, BAs further influence intracellular regulators related to CVD risk. They are ultimately involved in the occurrence and development of cardiovascular system diseases such as cardiomyopathy, atherosclerosis, arrhythmia, and heart failure by affecting the relevant regulatory factors of cardiovascular disease risk.

Figure 3.

A heatmap analysis of the expression of regulated genes and associated receptors during BA anabolism in DCM and HCM patients based on the accession number GSE141910 from the NCBI GEO database (www.ncbi.nlm.nih.gov/geo).