The Biosynthesis, Signaling, and Neurological Functions of Bile Acids

Abstract

Bile acids (BA) are amphipathic steroid acids synthesized from cholesterol in the liver. They act as detergents to expedite the digestion and absorption of dietary lipids and lipophilic vitamins. BA are also considered to be signaling molecules, being ligands of nuclear and cell-surface receptors, including farnesoid X receptor and Takeda G-protein receptor 5. Moreover, BA also activate ion channels, including the bile acid-sensitive ion channel and epithelial Na⁺ channel. BA regulate glucose and lipid metabolism by activating these receptors in peripheral tissues, such as the liver and brown and white adipose tissue. Recently, 20 different BA have been identified in the central nervous system. Furthermore, BA affect the function of neurotransmitter receptors, such as the muscarinic acetylcholine receptor and γ-aminobutyric acid receptor. BA are also known to be protective against neurodegeneration. Here, we review recent findings regarding the biosynthesis, signaling, and neurological functions of BA.

Keywords: ALS; Alzheimer’s disease; FXR; Huntington’s disease; Parkinson’s disease; SHP; TGR5; bile acids.

Figure 1

Synthesis of bile acids (BA). The classical pathway is initiated by cytochrome P450 7A1 (CYP7A1). CYP7A1 converts cholesterol to 7α-hydroxycholesterol. 7α-hydroxycholesterol is then converted to 7α-hydroxy-4-cholesten-3-one. Cytochrome P450 8B1 (CYP8B1) leads the production of CA from 7α-hydroxy-4-cholesten-3-one. 7α-hydroxy-4-cholesten-3-one is also converted to CDCA by cytochrome P450 27A1 (CYP27A1). The alternative pathway begins with converting cholesterol to (25R)-26-hydroxycholesterol by CYP27A1. Cytochrome P450 7B1 (CYP7B1) leads (25R)-26-hydroxycholesterol to CDCA. CDCA is converted to α-muricholic acid (MCA), and β-MCA. These BA are then conjugated with glycine or taurine. BA in rodents are also conjugated with taurine in the liver. BA synthesized in the liver are called primary BA. In the brain, 24S-hydroxycholesterol is converted from cholesterol by cytochrome P450 46A1 (CYP46A1). 24S-hydroxycholesterol is a precursor of 3β-hydroxy-5-cholenoic acid, which can be converted to CDCA through the intermediates (3β, 7α-dihydroxy-5-cholenoic acid and 7α-hydroxy-3-oxo-4-cholenoic acid). A large amount of (25R)-26-hydoxycholesterol incorporates to brain from circulation, and (25R)-26-hydoxycholesterol can also be converted to 3β-hydroxy-5-cholenoic acid.

Figure 2

Enterohepatic circulation. Bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2) are transporters mediating the secretion of bile acids (BA) from hepatocytes to the bile canaliculus in the liver. BA are stored in the gallbladder and secreted into the small intestine after a meal. Most BA (approximately 95%) are reabsorbed, whereas the remainder is excreted with feces. Apical sodium dependent bile acid transporter (ASBT) in the apical brush border of enterocytes takes BA into enterocytes. Ileal bile acid-binding protein (I-BABP) is related to the intracellular transport in enterocytes. The passage of BA through the basolateral membrane of enterocytes into the portal blood occurs through organic solute transporter (OST) α and β. BA released into the blood from the small intestine are transported into the liver by Na⁺-taurocholate co-transporting polypeptide (NTCP) or organic anion-transporting polypeptides (OATPs). These BA are then reconjugated and secreted with newly produced BA. This recycling system is termed enterohepatic circulation.

Figure 3

Bile acids (BA) activate receptors and ion channels. Nuclear receptors activated by BA include the farnesoid X receptor (FXR), pregnane X receptor (PXR), vitamin D receptor (VDR), liver X receptor (LXR), and glucocorticoid receptor (GR). Unconjugated BA might be able to cross the plasma membrane, and conjugated BA might cross the plasma membrane using transporters. Cell surface receptors activated by BA are Takeda G-protein receptor 5 (TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), M2 and M3 muscarinic receptors, and formyl-peptide receptor (FPR). Bile acid-sensitive ion channel (BASIC), epithelial Na⁺ channel (ENaC), and large-conductance Ca²⁺- and voltage-activated K⁺ (BK) channels are ion channels that are activated by BA. These receptors and ion channels are expressed in the brain.

Figure 4

Protective functions of bile acids (BA) against neurodegeneration. BA are known to prevent the accumulation of amyloid β peptides in Alzheimer’s disease; protect against mitochondrial damage in Parkinson’s disease; protect against apoptosis, mitochondrial damage, and ubiquitin accumulation in Huntington’s disease; and protect against apoptosis in amyotrophic lateral sclerosis.