Bile acid

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Bile acids are steroid acids found predominantly in the bile of mammals.

Production and distribution

They are produced in the liver by the oxidation of cholesterol, conjugated (with either the amino acid taurine or glycine, or a sulfate, or a glucuronide) and are stored in the gallbladder. Upon eating a meal containing fat, the contents of the gallbladder are secreted into the intestine. In humans, the rate limiting step is the addition of a hydroxyl group on position 7 of the steroid nucleus by the enzyme cholesterol 7 alpha-hydroxylase.) Bile acids serve multiple functions, which include: elimination of cholesterol from the body, driving the flow of bile to eliminate catabolites from the liver, serving to emulsify lipids and fat soluble vitamins in the intestine, and (likely) to aid reducing the bacteria flora found in the small intestine and biliary tract.

Synthesis of bile acids is a major consumer of cholesterol in most species (other than humans). The body synthesizes about 800 mg of cholesterol per day and about half of that is used for bile acid synthesis. In total about 20-30 grams of bile acids are secreted into the intestine daily; about 90% of excreted bile acids are reabsorbed (by active transport in the ileum) and recycled. This is referred to as the enterohepatic circulation.

Types

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 the presence and orientation of different numbers of hydroxyl groups. The four rings are labelled from left to right (as commonly drawn) A, B, C, and D, with the D-ring being smaller by one carbon than the other three. The hydroxyl groups have a choice of being in 2 positions, either up (or out) termed beta (often drawn by convention as a solid line), or down, termed alpha (seen as a dashed line in drawings). All bile acids have a hydroxyl group on position 3, which was derived from the parent molecule, cholesterol. In cholesterol, the 4 steroid rings are flat and the position of the 3-hydroxyl is beta. In many species, the initial step in the formation of a bile acid is the addition of a 7-alpha hydroxyl group. Subsequently, in the conversion from cholesterol to a bile acid, the junction between the first two steroid rings (A and B) is altered, making the molecule bent, and in this process, the 3-hydroxyl is converted to the alpha orientation. Thus, the default simplest bile acid (of 24 carbons) has two hydroxyl groups at positions 3-alpha and 7-alpha. The chemical name for this compound is 3-alpha,7-alpha-dihydroxy-5-beta-cholan-24-oic acid, or as it is commonly known, chenodeoxycholic acid. This bile acid was first isolated from the domestic goose, from which the "cheno" portion of the name was derived. Another bile acid, cholic acid (with 3 hydroxyl groups) had already been described, so the discovery of chenodeoxcholic acid (with 2 hydroxyl groups) made the new bile acid a "deoxycholic acid" in that it had one less hydroxyl group than cholic acid. The 5-beta portion of the name denotes the orientation of the junction between rings A and B of the steroid nucleus (in this case, they are bent). 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, which happens to be at the end of the side-chain. Chenodeoxycholic acid is made by many species, and is quite a functional bile acid. Its chief drawback lies in the ability of intestinal bacteria to remove the 7-alpha hydroxyl group, a process termed dehydroxylation. The resulting bile acid has only a 3-alpha hydroxyl group and is termed lithocholic acid (litho = stone). It is poorly water-soluble and rather toxic to cells. Bile acids formed by synthesis in the liver are termed "primary" bile acids, and those made by bacteria are termed "secondary" bile acids. As a result, chenodeoxycholic acid is a primary bile acid, and lithocholic acid is a secondary bile acid. To avoid the problems associated with the production of lithocholic acid, most species add a third hydroxyl group to chenodeoxycholic acid. In this manner, the subsequent removal of the 7-alpha hydroxyl group by intestinal bacteria will result in a less toxic, 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 16-alpha position was favored, particularly in birds. Later, this position was superseded by a large number of species selecting position 12-alpha. Primates (including humans) utilize 12-alpha for their third hydroxyl group position. The resulting primary bile acid in humans is 3-alpha,7-alpha,12-alpha-trihydroxy-5-beta-cholan-24-oic acid, or as it is commonly called, cholic acid. In the intestine, cholic acid is dehydroxylated to form the dihydroxy bile acid deoxycholic acid. In many vertebrate orders still subject to speciation, new species are discarding 12-alpha hydroxylation in favor of a hydroxy group on position 23 of the side-chain. It should be noted that vertebrate families and species exist that have experimented with and utilize just about every position imaginable on the steroid nucleus and side-chain.

The principal bile acids are:

In humans, the most important bile acids are cholic acid, deoxycholic acid, and chenodeoxycholic acid, Prior to secretion by the liver, they are conjugated with either the amino acid glycine or taurine. Conjugation increases their water solubility, preventing passive re-absorption once secreted into the small intestine. As a result, the concentration of bile acids in the small intestine can stay high enough to form micelles and solubilize lipids. The term "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.

Regulation

As surfactants or detergents, bile acids are potentially toxic to cells and their levels are tightly regulated. They function directly as signaling molecules in the liver and the intestines by activating a nuclear hormone receptor known as FXR also known by its gene name NR1H4. This results in inhibition of bile acid synthesis in the liver when bile acid levels are too high. Emerging evidence associates FXR activation with alterations in triglyceride metabolism, glucose metabolism and liver growth.

Clinical significance

Since bile acids are made from endogenous cholesterol, the enterohepatic circulation of bile acids may be disrupted as a way to lower cholesterol. This is the mechanism of action behind bile acid sequestrants. Bile acid sequestrants bind bile acids in the gut, preventing their reabsorption. The sequestered bile acids are then excreted in the feces.

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