Overview of Bile Acids Signaling and Perspective on the Signal of Ursodeoxycholic Acid, the Most Hydrophilic Bile Acid, in the Heart

Abstract

Bile acids (BA) are classically known as an important agent in lipid absorption and cholesterol metabolism. Nowadays, their role in glucose regulation and energy homeostasis are widely reported. BAs are involved in various cellular signaling pathways, such as protein kinase cascades, cyclic AMP (cAMP) synthesis, and calcium mobilization. They are ligands for several nuclear hormone receptors, including farnesoid X-receptor (FXR). Recently, BAs have been shown to bind to muscarinic receptor and Takeda G-protein-coupled receptor 5 (TGR5), both G-protein-coupled receptor (GPCR), independent of the nuclear hormone receptors. Moreover, BA signals have also been elucidated in other nonclassical BA pathways, such as sphingosine-1-posphate and BK (large conductance calcium- and voltage activated potassium) channels. Hydrophobic BAs have been proven to affect heart rate and its contraction. Elevated BAs are associated with arrhythmias in adults and fetal heart, and altered ratios of primary and secondary bile acid are reported in chronic heart failure patients. Meanwhile, in patients with liver cirrhosis, cardiac dysfunction has been strongly linked to the increase in serum bile acid concentrations. In contrast, the most hydrophilic BA, known as ursodeoxycholic acid (UDCA), has been found to be beneficial in improving peripheral blood flow in chronic heart failure patients and in protecting the heart against reperfusion injury. This review provides an overview of BA signaling, with the main emphasis on past and present perspectives on UDCA signals in the heart.

Keywords: bile acid; cardioprotection; heart; signaling; ursodeoxycholic acid.

Figure 1

The hydrophobicity of bile acids decrease with increase in OH groups. (GCA, glycocholic acid; GDCA, glycodeoxycholic acid; GCDCA, glycochenodeoxycholic acid; TCA, taurocholic acid; TDCA, taurodeoxycholic acid; TCDCA, taurochenodeoxycholic acid).

Figure 2

Proposed anti-apoptosis mechanism for UDCA cardioprotection against hypoxia. Pertussis toxin does not block the effect of UDCA on caspase-9, neutral SMase expression, ROS production, and Hif-1α expression in hypoxia-induced CMs. Beating rate is partially inhibited by PTX, suggestive of nonsensitive PTX pathway (pathways independent of Gα_i-coupled-receptor) involvement. Ursodeoxycholic acid cardioprotection has been reported to regulate the activation of survival signaling proteins (ERK 1/2 and Akt) and neutral SMase in hypoxia-induced CMs [104]. UDCA has been shown to downregulate caspase-9 protein expression and neutral SMase activity and upregulate phosphorylation of ERK 1/2 and Akt via Gαi-independent pathways (red line) to promote cardioprotection against the effects of CoCl₂. Meanwhile, UDCA has been shown to inhibit Hif-1α, ROS production, and caspase-9 protein expressions in CoCl₂-induced hypoxia CMs [91]. The data also suggests that UDCA cardioprotection in CoCl₂-induced hypoxia could be mediated through dependent Gαi pathways on CM beating rate (blue line). GPCR: G-protein-coupled receptor; Gαi, Gi alpha subunit is a G protein subunit that inhibits cAMP from production; Gβ, G-beta; Gγ, G-gamma; nSMase, neutral sphingomyelinase; UDCA, ursodeoxycholic acid; Hif-α, hypoxia inducible factor alpha; Hif-ẞ, hypoxia inducible factor beta; ROS, reactive oxygen species; Akt, protein kinase B; ERK, extracellular signal regulated kinase; PTX, pertussin toxin.

Figure 3

Proposed mechanisms for UDCA cardioprotection in maintaining normal [Ca²⁺]_i and HIF-1α level. Binding of UDCA to PTX-sensitive receptor partially improves cell survival. However, PTX does not block the effect of UDCA on [Ca²⁺]_i, HIF-1α translocation, and p53 protein expression against hypoxia. Cell viability is partially inhibited by PTX; dual pathway is suggested to be involved (Gα_i-coupled receptor-dependent and -independent pathways). Blue arrow, Gα_i-coupled receptor-dependent pathways; red arrow, Gα_i-coupled receptor-independent pathways. (UDCA, ursodeoxycholic acid; Gαi, G-alpha; ẞ, G-beta; γ, G-gamma; Hif-1 alpha, hypoxia inducible factor 1 alpha; [Ca²⁺]_i, intracellular calcium; p53, cellular tumor antigen p53).