Bile acid
Bile acids are steroid acids found predominantly in the bile of mammals and other vertebrates. Diverse bile acids are synthesized in the liver in peroxisomes. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts.
Primary bile acids are those synthesized by the liver. Secondary bile acids result from bacterial actions in the colon. In humans, taurocholic acid and glycocholic acid and taurochenodeoxycholic acid and glycochenodeoxycholic acid are the major bile salts. The salts of their 7-alpha-dehydroxylated derivatives, deoxycholic acid and lithocholic acid, are also found, with derivatives of cholic, chenodeoxycholic and deoxycholic acids accounting for over 90% of human biliary bile acids.
Description
Bile acids comprise about 80% of the organic compounds in bile. An increased secretion of bile acids produces an increase in bile flow. Bile acids facilitate digestion of dietary fats and oils. They serve as micelle-forming surfactants, which encapsulate nutrients, facilitating their absorption. These micelles are suspended in the chyme before further processing. Bile acids also have hormonal actions throughout the body, particularly through the farnesoid X receptor and GPBAR1.Production
Primary bile acids
Bile acid synthesis occurs in liver cells, which synthesize primary bile acids via cytochrome P450-mediated oxidation of cholesterol in a multi-step process. Approximately 600 mg of bile salts are synthesized daily to replace bile acids lost in the feces, although, as described below, much larger amounts are secreted, reabsorbed in the gut and recycled.The rate-limiting step in synthesis is the addition of a hydroxyl group of the 7th position of the steroid nucleus by the enzyme cholesterol 7 alpha-hydroxylase. This enzyme is down-regulated by cholic acid, up-regulated by cholesterol and is inhibited by the actions of the ileal hormone FGF15/19.
Prior to secreting any of the bile acids, liver cells conjugate them with either glycine or taurine, to form a total of 8 possible conjugated primary bile acids. These conjugated bile acids are often referred to as bile salts. The pKa of the unconjugated bile acids are between 5 and 6.5, and the pH of the duodenum ranges between 3 and 5, so when unconjugated bile acids are in the duodenum, they are almost always protonated, which makes them relatively insoluble in water. Conjugating bile acids with amino acids lowers the pKa of the bile-acid/amino-acid conjugate to between 1 and 4. Thus conjugated bile acids are almost always in their deprotonated form in the duodenum, which makes them much more water-soluble and much more able to fulfil their physiological function of emulsifying fats.
Secondary bile acids
Once secreted into the lumen of the intestine, bile salts are modified by gut bacteria. They are partially dehydroxylated. Their glycine and taurine groups are removed to give the secondary bile acids, deoxycholic acid and lithocholic acid. Cholic acid is converted into deoxycholic acid and chenodeoxycholic acid into lithocholic acid. All four of these bile acids are recycled, in a process known as enterohepatic circulation.Functions
Lipid digestion
As molecules with hydrophobic and hydrophilic regions, conjugated bile salts sit at the lipid/water interface and, above the right concentration, form micelles. The added solubility of conjugated bile salts aids in their function by preventing passive re-absorption in the small intestine. As a result, the concentration of bile acids/salts in the small intestine is high enough to form micelles and solubilize lipids. "Critical micellar concentration" refers to both an intrinsic property of the bile acid itself and amount of bile acid necessary to function in the spontaneous and dynamic formation of micelles. Bile acid-containing micelles aid lipases to digest lipids and bring them near the intestinal brush border membrane, which results in fat absorption.Synthesis of bile acids is a major route of cholesterol metabolism in most species other than humans. The body produces about 800 mg of cholesterol per day and about half of that is used for bile acid synthesis producing 400–600 mg daily. Human adults secrete between 12 and 18 g of bile acids into the intestine each day, mostly after meals. The bile acid pool size is between 4–6 g, which means that bile acids are recycled several times each day. About 95% of bile acids are reabsorbed by active transport in the ileum and recycled back to the liver for further secretion into the biliary system and gallbladder. This enterohepatic circulation of bile acids allows a low rate of synthesis, only about 0.3 g/day, but with large amounts being secreted into the intestine.
Bile acids have other functions, including eliminating cholesterol from the body, driving the flow of bile to eliminate certain catabolites, emulsifying fat-soluble vitamins to enable their absorption, and aiding in motility and the reduction of the bacteria flora found in the small intestine and biliary tract.
Cell signalling
Bile acids have metabolic actions in the body resembling those of hormones, acting through two specific receptors, the farnesoid X receptor and G protein-coupled bile acid receptor TGR5. They bind less specifically to some other receptors and have been reported to regulate the activity of certain enzymes and ion channels, and the biosynthesis of diverse substances including endogenous fatty acid ethanolamides, which have key roles in several physiological pathways including stress and pain responses, appetite, and lifespan.Structure and synthesis
Bile salts constitute a large family of molecules, composed of a steroid structure with four rings, a five- or eight-carbon side-chain terminating in a carboxylic acid, and several hydroxyl groups, the number and orientation of which is different among the specific bile salts. The four rings are labeled A, B, C, and D, from the farthest to the closest to the side chain with the carboxyl group. The D-ring is smaller by one carbon than the other three. The structure is commonly drawn with A at the left and D at the right. The hydroxyl groups can be in either of two configurations: either up, termed beta, or down, termed alpha. All bile acids have a 3-hydroxyl group, derived from the parent molecule, cholesterol, in which the 3-hydroxyl is beta.Image:Steroid lettering numbering.svg|class=skin-invert-image|thumb|320px|IUPAC recommended ring lettering and atom numbering of the steroid skeleton. The four rings A-D form a sterane core.
The initial step in the classical pathway of hepatic synthesis of bile acids is the enzymatic addition of a 7α hydroxyl group by cholesterol 7α-hydroxylase forming 7α-hydroxycholesterol. This is then metabolised to 7α-hydroxy-4-cholesten-3-one. There are multiple steps in bile acid synthesis requiring 14 enzymes in all. These result in the junction between the first two steroid rings being altered, making the molecule bent; in this process, the 3-hydroxyl is converted to the α orientation. The simplest 24-carbon bile acid has two hydroxyl groups at positions 3α and 7α. This is 3α,7α-dihydroxy-5β-cholan-24-oic acid, or, as more usually known, chenodeoxycholic acid. This bile acid was first isolated from the domestic goose, from which the "cheno" portion of the name was derived. The 5β in the name denotes the orientation of the junction between rings A and B of the steroid nucleus. The term "cholan" denotes a particular steroid structure of 24 carbons, and the "24-oic acid" indicates that the carboxylic acid is found at position 24, at the end of the side-chain. Chenodeoxycholic acid is made by many species, and is the prototypic functional bile acid.
An alternative pathway of bile acid synthesis is initiated by mitochondrial sterol 27-hydroxylase, expressed in liver, and also in macrophages and other tissues. CYP27A1 contributes significantly to total bile acid synthesis by catalyzing sterol side chain oxidation, after which cleavage of a three-carbon unit in the peroxisomes leads to formation of a C24 bile acid. Minor pathways initiated by 25-hydroxylase in the liver and 24-hydroxylase in the brain also may contribute to bile acid synthesis. 7α-hydroxylase generates oxysterols, which may be further converted in the liver to CDCA.
Cholic acid, 3α,7α,12α-trihydroxy-5β-cholan-24-oic acid, the most abundant bile acid in humans and many other species, was discovered before chenodeoxycholic acid. It is a tri-hydroxy-bile acid with 3 hydroxyl groups. In its synthesis in the liver, 12α hydroxylation is performed by the additional action of CYP8B1. As this had already been described, the discovery of chenodeoxycholic acid made this new bile acid a "deoxycholic acid" in that it had one fewer hydroxyl group than cholic acid.
Deoxycholic acid is formed from cholic acid by 7-dehydroxylation, resulting in 2 hydroxyl groups. This process with chenodeoxycholic acid results in a bile acid with only a 3α hydroxyl group, termed lithocholic acid having been identified first in a gallstone from a calf. It is poorly water-soluble and rather toxic to cells.
Different vertebrate families have evolved to use modifications of most positions on the steroid nucleus and side-chain of the bile acid structure. To avoid the problems associated with the production of lithocholic acid, most species add a third hydroxyl group to chenodeoxycholic acid. The subsequent removal of the 7α hydroxyl group by intestinal bacteria will then result in a less toxic but still-functional dihydroxy bile acid. Over the course of vertebrate evolution, a number of positions have been chosen for placement of the third hydroxyl group. Initially, the 16α position was favored, in particular in birds. Later, this position was superseded in a large number of species selecting the 12α position. Primates utilize 12α for their third hydroxyl group position, producing cholic acid. In mice and other rodents, 6β hydroxylation forms muricholic acids. Pigs have 6α hydroxylation in hyocholic acid, and other species have a hydroxyl group on position 23 of the side-chain.
Many other bile acids have been described, often in small amounts, resulting from bacterial enzymatic or other modifications. The "iso-" epimers have the 3-hydroxyl group in the β position. The "allo-" epimers have the 5α configuration, which changes the relative position of the A and B rings.
Ursodeoxycholic acid was first isolated from bear bile, which has been used medicinally for centuries. Its structure resembles chenodeoxycholic acid but with the 7-hydroxyl group in the β position.
Obeticholic acid, 6α-ethyl-chenodeoxycholic acid, is a semi-synthetic bile acid with greater activity as an FXR agonist, which has been developed as a pharmaceutical agent in certain liver diseases.