Bile acids: chemistry, physiology, and pathophysiology

Abstract

The family of bile acids includes a group of molecular species of acidic steroids with very peculiar physical-chemical and biological characteristics. They are synthesized by the liver from cholesterol through several complementary pathways that are controlled by mechanisms involving fine-tuning by the levels of certain bile acid species. Although their best-known role is their participation in the digestion and absorption of fat, they also play an important role in several other physiological processes. Thus, genetic abnormalities accounting for alterations in their synthesis, biotransformation and/or transport may result in severe alterations, even leading to lethal situations for which the sole therapeutic option may be liver transplantation. Moreover, the increased levels of bile acids reached during cholestatic liver diseases are known to induce oxidative stress and apoptosis, resulting in damage to the liver parenchyma and, eventually, extrahepatic tissues. When this occurs during pregnancy, the outcome of gestation may be challenged. In contrast, the physical-chemical and biological properties of these compounds have been used as the bases for the development of drugs and as pharmaceutical tools for the delivery of active agents.

Figure 1

Structures of the most abundant bile acids in humans, and their glycine and taurine conjugates.

Figure 2

Stereostructure of cholic acid. A: Space-filling model; B: Calculated molecular lipophilic potential[147]. Blue colour shows polar surface and red colour shows apolar surface; C: Cartoon representation (as introduced by Small[148]).

Figure 3

Schematic representation of bile acid synthesis by the classical neutral pathway. AKR1C4: 3α-hydroxysteroid dehydrogenase; AKR1D1: Δ4–3-oxosteroid-5β-reductase; AMACR: Alpha methylacyl-CoA racemase; BAAT: Bile acid; CoA: Amino acid N-acyltransferase (¹A minor cytosolic fraction does also exist); BACS: Bile acid CoA synthetase; BCOX: Branched-chain acyl CoA oxidase; BDP: D-bifunctional protein hydratase; CYP27A1: Sterol 27-hydroxylase; CYP7A1: Cholesterol 7α-hydroxylase; CYP8B1: Sterol 12α-hydroxylase; HSD3B7: 3β-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase; SCPx: Sterol carrier protein X; VLCS: Very long-chain acyl CoA synthetase; ER: Endoplasmic reticulum.