The Role of Bile Acids in the Human Body and in the Development of Diseases

Abstract

Bile acids are specific and quantitatively important organic components of bile, which are synthesized by hepatocytes from cholesterol and are involved in the osmotic process that ensures the outflow of bile. Bile acids include many varieties of amphipathic acid steroids. These are molecules that play a major role in the digestion of fats and the intestinal absorption of hydrophobic compounds and are also involved in the regulation of many functions of the liver, cholangiocytes, and extrahepatic tissues, acting essentially as hormones. The biological effects are realized through variable membrane or nuclear receptors. Hepatic synthesis, intestinal modifications, intestinal peristalsis and permeability, and receptor activity can affect the quantitative and qualitative bile acids composition significantly leading to extrahepatic pathologies. The complexity of bile acids receptors and the effects of cross-activations makes interpretation of the results of the studies rather difficult. In spite, this is a very perspective direction for pharmacology.

Keywords: bile acids; bile acids receptors; pathogenesis.

Figure 1

Interaction of bile acids with various cellular molecules: non-receptor-mediated interaction of bile acid with big potassium, calcium-activated channels, which leads to K+ outflow, hyperpolarization, and relaxation of vascular smooth muscles (1) and interaction of bile acid with nuclear receptors (2). In the cytoplasm, bile acid binding to FXR triggers dimerization with RXR, which leads to translocation of FXR into the nucleus, where FXR binds to regulatory elements of the target gene. Downward (red) and upward (blue) arrows indicate down and up-regulation of molecules, respectively. MSX2 and osterix are osteogenic transcription factors. Interaction of bile acid with GPCR, which can lead to a negative chronotropic response (for M₂R) in cardiac myocytes and the generation of NO (for M₃R and GPBAR1) in endothelial cells (3). AT2R: type 2 angiotensin receptor; BKCa: large channels activated by potassium and calcium; CD11b: cluster of differentiation 11b; ET-1: endothelin-1; interleukin-1 and -6; M₂R: muscarinic receptor subtype 2; M₃R: muscarinic receptor subtype 3; MSX2: homeobox muscle segment 2; NOS3: nitric oxide synthase 3. Figure adapted with permission from Ref. [3] 2011, Khurana, S. et al.

Figure 2

Possible primary signaling pathways (GPBAR1 and FXR) and the potential role of endogenous bile acids in models of neurodegenerative disorders. BA—bile acids, C—cholesterol, FXR—farnesoid X receptor, GPBAR1—G protein-coupled bile acid receptor 1.