Bile acids are
steroidA steroid is a terpenoid lipid characterized by its sterane core and additional functional groups. The core is a carbon structure of four fused rings: three cyclohexane rings and one cyclopentane ring. The steroids vary by the functional groups attached to these rings and the oxidation state of the...
acidAn acid is traditionally considered any chemical compound that, when dissolved in water, gives a solution with a hydrogen ion activity greater than in pure water, i.e. a pH less than 7.0...
s found predominantly in the
bileBile or gall is a bitter yellowish, blue and green fluid secreted by hepatocytes from the liver of most vertebrates. In many species, bile is stored in the gallbladder between meals and upon eating is discharged into the duodenum where the bile aids the process of digestion of lipids by...
of mammals. Bile salts are bile acids conjugated to
glycineGlycine is an organic compound with the formula NH2CH2COOH. With only a hydrogen atom as its side chain, glycine is the smallest of the 20 amino acids commonly found in proteins....
or
taurineTaurine, or 2-aminoethanesulfonic acid, is an organic acid. It is also a major constituent of bile and can be found in the lower intestine and in small amounts in the tissues of many animals, including humans. Taurine is a derivative of the sulfur-containing amino acid, cysteine...
. In humans,
taurocholic acidTaurocholic acid, known also as cholaic acid, cholyltaurine, or acidum cholatauricum, is a deliquescent yellowish crystalline bile acid involved in the emulsification of fats. It occurs as a sodium salt in the bile of mammals. It is a conjugate of cholic acid with taurine...
and
glycocholic acidGlycocholic acid, or cholylglycine, is a crystalline bile acid involved in the emulsification of fats. It occurs as a sodium salt in the bile of mammals. It is a conjugate of cholic acid with glycine. Its anion is called glycocholate....
(derivatives of
cholic acidCholic acid is a bile acid, a white crystalline substance insoluble in water , with a melting point of 200-201 °C. Salts of cholic acid are called cholates. Cholic acid, along with chenodeoxycholic acid, is one of two major bile acids produced by the liver where it is synthesized from cholesterol...
) represent approximately eighty percent of all bile salts. The two major bile acids are
cholic acidCholic acid is a bile acid, a white crystalline substance insoluble in water , with a melting point of 200-201 °C. Salts of cholic acid are called cholates. Cholic acid, along with chenodeoxycholic acid, is one of two major bile acids produced by the liver where it is synthesized from cholesterol...
, and
chenodeoxycholic acidChenodeoxycholic acid is a bile acid. It occurs as a white crystalline substance insoluble in water but soluble in alcohol and acetic acid, with melting point at 165-167 °C. Salts of this carboxylic acid are called chenodeoxycholates...
. Bile acids,
glycineGlycine is an organic compound with the formula NH2CH2COOH. With only a hydrogen atom as its side chain, glycine is the smallest of the 20 amino acids commonly found in proteins....
and
taurineTaurine, or 2-aminoethanesulfonic acid, is an organic acid. It is also a major constituent of bile and can be found in the lower intestine and in small amounts in the tissues of many animals, including humans. Taurine is a derivative of the sulfur-containing amino acid, cysteine...
conjugates, and 7-alpha-dehydroxylated derivatives (
deoxycholic acidDeoxycholic acid, also known as deoxycholate, cholanoic acid, and 3α,12α-dihydroxy-5β-cholanate, is a bile acid. Deoxycholic acid is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria. The two primary bile acids secreted by the liver are cholic acid and...
and
lithocholic acidLithocholic acid is a bile acid which acts as a detergent to solubilize fats for absorption. Biosynthetically, it is made from chenodeoxycholic acid by bacterial action in the colon. It has been implicated in human and experimental animal carcinogenesis. Dietary fiber can bind to lithocholic...
) are all found in human intestinal bile. An increase in bile flow is exhibited with an increased secretion of bile acids.
Bile acids are
steroidA steroid is a terpenoid lipid characterized by its sterane core and additional functional groups. The core is a carbon structure of four fused rings: three cyclohexane rings and one cyclopentane ring. The steroids vary by the functional groups attached to these rings and the oxidation state of the...
acidAn acid is traditionally considered any chemical compound that, when dissolved in water, gives a solution with a hydrogen ion activity greater than in pure water, i.e. a pH less than 7.0...
s found predominantly in the
bileBile or gall is a bitter yellowish, blue and green fluid secreted by hepatocytes from the liver of most vertebrates. In many species, bile is stored in the gallbladder between meals and upon eating is discharged into the duodenum where the bile aids the process of digestion of lipids by...
of mammals. Bile salts are bile acids conjugated to
glycineGlycine is an organic compound with the formula NH2CH2COOH. With only a hydrogen atom as its side chain, glycine is the smallest of the 20 amino acids commonly found in proteins....
or
taurineTaurine, or 2-aminoethanesulfonic acid, is an organic acid. It is also a major constituent of bile and can be found in the lower intestine and in small amounts in the tissues of many animals, including humans. Taurine is a derivative of the sulfur-containing amino acid, cysteine...
. In humans,
taurocholic acidTaurocholic acid, known also as cholaic acid, cholyltaurine, or acidum cholatauricum, is a deliquescent yellowish crystalline bile acid involved in the emulsification of fats. It occurs as a sodium salt in the bile of mammals. It is a conjugate of cholic acid with taurine...
and
glycocholic acidGlycocholic acid, or cholylglycine, is a crystalline bile acid involved in the emulsification of fats. It occurs as a sodium salt in the bile of mammals. It is a conjugate of cholic acid with glycine. Its anion is called glycocholate....
(derivatives of
cholic acidCholic acid is a bile acid, a white crystalline substance insoluble in water , with a melting point of 200-201 °C. Salts of cholic acid are called cholates. Cholic acid, along with chenodeoxycholic acid, is one of two major bile acids produced by the liver where it is synthesized from cholesterol...
) represent approximately eighty percent of all bile salts. The two major bile acids are
cholic acidCholic acid is a bile acid, a white crystalline substance insoluble in water , with a melting point of 200-201 °C. Salts of cholic acid are called cholates. Cholic acid, along with chenodeoxycholic acid, is one of two major bile acids produced by the liver where it is synthesized from cholesterol...
, and
chenodeoxycholic acidChenodeoxycholic acid is a bile acid. It occurs as a white crystalline substance insoluble in water but soluble in alcohol and acetic acid, with melting point at 165-167 °C. Salts of this carboxylic acid are called chenodeoxycholates...
. Bile acids,
glycineGlycine is an organic compound with the formula NH2CH2COOH. With only a hydrogen atom as its side chain, glycine is the smallest of the 20 amino acids commonly found in proteins....
and
taurineTaurine, or 2-aminoethanesulfonic acid, is an organic acid. It is also a major constituent of bile and can be found in the lower intestine and in small amounts in the tissues of many animals, including humans. Taurine is a derivative of the sulfur-containing amino acid, cysteine...
conjugates, and 7-alpha-dehydroxylated derivatives (
deoxycholic acidDeoxycholic acid, also known as deoxycholate, cholanoic acid, and 3α,12α-dihydroxy-5β-cholanate, is a bile acid. Deoxycholic acid is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria. The two primary bile acids secreted by the liver are cholic acid and...
and
lithocholic acidLithocholic acid is a bile acid which acts as a detergent to solubilize fats for absorption. Biosynthetically, it is made from chenodeoxycholic acid by bacterial action in the colon. It has been implicated in human and experimental animal carcinogenesis. Dietary fiber can bind to lithocholic...
) are all found in human intestinal bile. An increase in bile flow is exhibited with an increased secretion of bile acids. The main function of bile acid is to facilitate the formation of micelles, which promotes processing of dietary fat.
Production and distribution
Bile acids are made in the
liverThe liver is a vital organ present in vertebrates and some other animals; it has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
by the cytochrome P450-mediated oxidation of
cholesterolCholesterol is a lipidic, waxy steroid found in the cell membranes and transported in the blood plasma of all animals. It is an essential component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity...
. They are conjugated with
taurineTaurine, or 2-aminoethanesulfonic acid, is an organic acid. It is also a major constituent of bile and can be found in the lower intestine and in small amounts in the tissues of many animals, including humans. Taurine is a derivative of the sulfur-containing amino acid, cysteine...
or the amino acid
glycineGlycine is an organic compound with the formula NH2CH2COOH. With only a hydrogen atom as its side chain, glycine is the smallest of the 20 amino acids commonly found in proteins....
, or with a
sulfateIn inorganic chemistry, a sulfate is a salt of sulfuric acid.-Chemical properties:...
or a
glucuronideA glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond...
, and are then stored in the
gallbladderThe gallbladder is a small non-vital organ that aids in the digestive process and stores bile produced in the liver.-Human anatomy:...
. 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. Upon eating a meal, the contents of the gallbladder are secreted into the
intestineIn anatomy, the intestine is the segment of the alimentary canal extending from the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
, where bile acids serve the purpose of emulsifying dietary fats. Bile acids serve other functions, including eliminating cholesterol from the body, driving the flow of bile to eliminate catabolites from the liver, emulsifying lipids and fat soluble vitamins in the intestine, and aiding in the reduction of the bacteria flora found in the small intestine and biliary tract.
Bile acid refers to the protonated (-COOH) form.
Bile salt refers to the deprotonated or ionized (-COO
-) form. Conjugated bile acids are more efficient at emulsifying fats because at intestinal pH, they are more ionized than unconjugated bile acids.
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. In total about 20-30 grams of bile acids are secreted into the
intestineIn anatomy, the intestine is the segment of the alimentary canal extending from the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...
daily. about 90% of excreted bile acids are reabsorbed by
active transportActive transport is the mediated process of moving particles across a biological membrane against a concentration gradient. If the process uses chemical energy, such as from adenosine triphosphate , it is termed primary active transport. Secondary active transport involves the use of an...
in the
ileumThe ileum is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine may be used instead of ileum.The ileum follows the duodenum...
and recycled in what is referred to as the
enterohepatic circulationEnterohepatic circulation refers to the circulation of biliary acids from the liver, where they are produced and secreted in the bile, to the small intestine, where it aids in digestion of fats and other substances, back to the liver....
. Bile is also used to break down fat globules into tiny droplets. Bile from slaughtered animals can be used in the preparation of soap.
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 labeled 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 acidCholic acid is a bile acid, a white crystalline substance insoluble in water , with a melting point of 200-201 °C. Salts of cholic acid are called cholates. Cholic acid, along with chenodeoxycholic acid, is one of two major bile acids produced by the liver where it is synthesized from cholesterol...
,
deoxycholic acidDeoxycholic acid, also known as deoxycholate, cholanoic acid, and 3α,12α-dihydroxy-5β-cholanate, is a bile acid. Deoxycholic acid is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria. The two primary bile acids secreted by the liver are cholic acid and...
, and
chenodeoxycholic acidChenodeoxycholic acid is a bile acid. It occurs as a white crystalline substance insoluble in water but soluble in alcohol and acetic acid, with melting point at 165-167 °C. Salts of this carboxylic acid are called chenodeoxycholates...
. Prior to secretion by the liver, they are conjugated with either the amino acid glycine or taurine. Conjugation increases 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. "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
surfactantSurfactants are wetting agents that lower the surface tension of a liquid, allowing easier spreading, and lower the interfacial tension between two liquids.- Etymology :The term surfactant is a blend of surface active agent...
s or
detergentA detergent is a material intended to assist cleaning. The term is sometimes used to differentiate between soap and other surfactants used for cleaning...
s, bile acids are potentially toxic to cells, and their concentrations are tightly regulated. They function as a signaling molecule in the liver and the intestines by activating a nuclear hormone receptor,
FXRThe farnesoid X receptor , also known as NR1H4 is a nuclear hormone receptor with activity similar to that seen in other steroid receptors such as estrogen or progesterone but more similar in form to PPAR, LXR and RXR. FXR is encoded by the gene.FXR is expressed at high levels in the liver and...
, also known by its gene name . Such activation inhibits synthesis of bile acid in the liver when bile acid levels are too high. Emerging evidence associates FXR activation with alterations in
triglycerideis a glyceride in which the glycerol is esterified with three fatty acids. It is the main constituent of vegetable oil and animal fats.- Chemical structure :...
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 to lower cholesterol.
Bile acid sequestrantThe bile acid sequestrants are a group of medications used to bind certain components of bile in the gastrointestinal tract. They disrupt the enterohepatic circulation of bile acids by sequestering them and preventing their reabsorption from the gut...
s bind bile acids in the gut, preventing reabsorption. In so doing, more endogenous cholesterol is shunted into the production of bile acids, thereby lowering cholesterol levels. The sequestered bile acids are then excreted in the feces.
Tests for bile acids are useful in both human and veterinary medicine, as they help to diagnose a number of conditions, including
cholestasisIn medicine, cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system such as can occur from a gallstone or malignancy and metabolic types of...
,
portosystemic shuntA portosystemic shunt , also known as a liver shunt, is a bypass of the liver by the body's circulatory system. It can be either a congenital or acquired condition....
, and
hepatic microvascular dysplasiaHepatic microvascular dysplasia or Portal Atresia is a disorder where mixing of venous blood and arterial blood in the liver occurs at the microscopic level. It occurs most commonly in certain dog breeds such as the Cairn and Yorkshire terriers although any dog breed may be at risk....
.
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