Bile acids are
steroid
A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
acid
In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a sequ ...
s found predominantly in the
bile
Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver bile ...
of
mammal
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
s and other
vertebrate
Vertebrates () comprise all animal taxa within the subphylum Vertebrata () ( chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, ...
s. Diverse bile acids are synthesized in the
liver
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
.
Bile acids are conjugated with
taurine
Taurine (), or 2-aminoethanesulfonic acid, is an organic compound that is widely distributed in animal tissues. It is a major constituent of bile and can be found in the large intestine, and accounts for up to 0.1% of total human body weight. I ...
or
glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
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
Taurocholic 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 conjugat ...
and
glycocholic acid
Glycocholic 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.
See also
...
(derivatives of
cholic acid
Cholic acid, also known as 3α,7α,12α-trihydroxy-5β-cholan-24-oic acid is a primary bile acid that is insoluble in water (soluble in alcohol and acetic acid), it is a white crystalline substance. Salts of cholic acid are called cholates. Chol ...
) and
taurochenodeoxycholic acid
Taurochenodeoxycholic acid is a bile acid formed in the liver of most species, including humans, by conjugation of chenodeoxycholic acid with taurine. It is secreted into bile and then into intestine. It is usually ionized at physiologic pH, alth ...
and
glycochenodeoxycholic acid
Glycochenodeoxycholic acid is a bile salt formed in the liver from chenodeoxycholic acid and glycine, usually found as the sodium salt
Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the ...
(derivatives of
chenodeoxycholic acid
Chenodeoxycholic acid (CDCA; also known as chenodesoxycholic acid, chenocholic acid and 3α,7α-dihydroxy-5β-cholan-24-oic acid) is a bile acid. Salts of this carboxylic acid are called chenodeoxycholates. Chenodeoxycholic acid is one of the mai ...
) are the major bile salts. They are roughly equal in concentration.
The salts of their 7-alpha-dehydroxylated derivatives,
deoxycholic acid
Deoxycholic acid 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 chenodeoxycholic acid. Bacteria ...
and
lithocholic acid
Lithocholic acid, also known as 3α-hydroxy-5β-cholan-24-oic acid or LCA, is a bile acid that acts as a detergent to solubilize fats for absorption. Bacterial action in the colon produces LCA from chenodeoxycholic acid by reduction of the hydro ...
, are also found, with derivatives of cholic, chenodeoxycholic and deoxycholic acids accounting for over 90% of human biliary bile acids.
[
Bile acids comprise about 80% of the organic compounds in bile (others are ]phospholipids
Phospholipids, are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...
and cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
).[ 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
A micelle () or micella () (plural micelles or micellae, respectively) is an aggregate (or supramolecular assembly) of surfactant amphipathic lipid molecules dispersed in a liquid, forming a colloidal suspension (also known as associated coll ...
-forming surfactants, which encapsulate nutrients, facilitating their absorption. These micelles are suspended in the chyme before further processing. Bile acids also have hormonal
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required f ...
actions throughout the body, particularly through the farnesoid X receptor and GPBAR1
The G protein-coupled bile acid receptor 1 (GPBAR1) also known G-protein coupled receptor 19 (GPCR19), membrane-type receptor for bile acids (M-BAR) or TGR5 as is a protein that in humans is encoded by the ''GPBAR1'' gene.
Function
This gene ...
(also known as TGR5).
Production
Primary bile acids
Bile acid synthesis occurs in liver cells
A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass.
These cells are involved in:
* Protein synthesis
* Protein storage
* Transformation of carbohydrates
* Synthesis of cholesterol, ...
, which synthesize primary bile acids (cholic acid
Cholic acid, also known as 3α,7α,12α-trihydroxy-5β-cholan-24-oic acid is a primary bile acid that is insoluble in water (soluble in alcohol and acetic acid), it is a white crystalline substance. Salts of cholic acid are called cholates. Chol ...
and chenodeoxycholic acid
Chenodeoxycholic acid (CDCA; also known as chenodesoxycholic acid, chenocholic acid and 3α,7α-dihydroxy-5β-cholan-24-oic acid) is a bile acid. Salts of this carboxylic acid are called chenodeoxycholates. Chenodeoxycholic acid is one of the mai ...
in humans) via cytochrome P450
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
-mediated oxidation of cholesterol
Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...
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 chemical kinetics, the overall rate of a reaction is often approximately determined by the slowest step, known as the rate-determining step (RDS or RD-step or r/d step) or rate-limiting step. For a given reaction mechanism, the prediction of th ...
in synthesis is the addition of a hydroxyl group of the 7th position of the steroid nucleus by the enzyme cholesterol 7 alpha-hydroxylase
Cholesterol 7 alpha-hydroxylase also known as cholesterol 7-alpha-monooxygenase or cytochrome P450 7A1 (CYP7A1) is an enzyme that in humans is encoded by the gene which has an important role in cholesterol metabolism. It is a cytochrome P450 enz ...
. This enzyme is down-regulated by cholic acid, up-regulated by cholesterol and is inhibited by the actions of the ileal
The 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 ...
hormone
A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required ...
FGF15/19
FGF15/19 refers to two orthologous fibroblast growth factors which share 50% aminoacid identity and have similar functions.
FGF15 was described in the mouse; FGF19 was found in humans and other species. They share physiological functions and ...
.
Prior to secreting any of the bile acids (primary or secondary, see below), liver cells conjugate them with either glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
or taurine
Taurine (), or 2-aminoethanesulfonic acid, is an organic compound that is widely distributed in animal tissues. It is a major constituent of bile and can be found in the large intestine, and accounts for up to 0.1% of total human body weight. I ...
, to form a total of 8 possible conjugated 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 (HA form), 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 (A-) form in the duodenum, which makes them much more water-soluble and much more able to fulfil their physiologic 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
Deoxycholic acid 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 chenodeoxycholic acid. Bacteria ...
and lithocholic acid
Lithocholic acid, also known as 3α-hydroxy-5β-cholan-24-oic acid or LCA, is a bile acid that acts as a detergent to solubilize fats for absorption. Bacterial action in the colon produces LCA from chenodeoxycholic acid by reduction of the hydro ...
. 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
Enterohepatic circulation refers to the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver. Ent ...
.
Functions
Lipids digestion
As molecules with hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, t ...
and hydrophilic
A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press.
In contrast, hydrophobes are ...
regions, conjugated bile salts sit at the lipid/water interface and, above the right concentration, form micelles
A micelle () or micella () (plural micelles or micellae, respectively) is an aggregate (or supramolecular assembly) of surfactant amphipathic lipid molecules dispersed in a liquid, forming a colloidal suspension (also known as associated coll ...
. 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
Lipase ( ) is a family of enzymes that catalyzes the hydrolysis of fats. Some lipases display broad substrate scope including esters of cholesterol, phospholipids, and of lipid-soluble vitamins and sphingomyelinases; however, these are usually tr ...
to digest lipids and bring them near the intestinal brush border
A brush border (striated border or brush border membrane) is the microvilli-covered surface of simple cuboidal and simple columnar epithelium found in different parts of the body. Microvilli are approximately 100 nanometers in diameter and their ...
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 cellular biology, ''active transport'' is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellul ...
in the ileum
The 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 ma ...
and recycled back to the liver for further secretion into the biliary system and gallbladder. This enterohepatic circulation
Enterohepatic circulation refers to the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver. Ent ...
of bile acids allows a low rate of synthesis, only about 0.3g/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 (including bilirubin
Bilirubin (BR) (Latin for "red bile") is a red-orange compound that occurs in the normal catabolic pathway that breaks down heme in vertebrates. This catabolism is a necessary process in the body's clearance of waste products that arise from the ...
), 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
The G protein-coupled bile acid receptor 1 (GPBAR1) also known G-protein coupled receptor 19 (GPCR19), membrane-type receptor for bile acids (M-BAR) or TGR5 as is a protein that in humans is encoded by the ''GPBAR1'' gene.
Function
This gene ...
/ 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 synthesis of diverse substances including endogenous fatty acid ethanolamides.
Structure and synthesis
File:Cholic acid.svg, Cholic acid
Cholic acid, also known as 3α,7α,12α-trihydroxy-5β-cholan-24-oic acid is a primary bile acid that is insoluble in water (soluble in alcohol and acetic acid), it is a white crystalline substance. Salts of cholic acid are called cholates. Chol ...
File:Glycocholsäure.svg, Glycocholic acid
Glycocholic 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.
See also
...
File:Taurocholic acid.svg, Taurocholic acid
Taurocholic 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 conjugat ...
File:Deoxycholic acid.svg, Deoxycholic acid
Deoxycholic acid 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 chenodeoxycholic acid. Bacteria ...
File:Chenodeoxycholic acid.svg, Chenodeoxycholic acid
Chenodeoxycholic acid (CDCA; also known as chenodesoxycholic acid, chenocholic acid and 3α,7α-dihydroxy-5β-cholan-24-oic acid) is a bile acid. Salts of this carboxylic acid are called chenodeoxycholates. Chenodeoxycholic acid is one of the mai ...
File:Glycochenodeoxycholic acid.svg, Glycochenodeoxycholic acid
Glycochenodeoxycholic acid is a bile salt formed in the liver from chenodeoxycholic acid and glycine, usually found as the sodium salt
Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the ...
File:Taurochenodeoxycholic acid.svg, Taurochenodeoxycholic acid
Taurochenodeoxycholic acid is a bile acid formed in the liver of most species, including humans, by conjugation of chenodeoxycholic acid with taurine. It is secreted into bile and then into intestine. It is usually ionized at physiologic pH, alth ...
File:Lithocholic acid acsv.svg, Lithocholic acid
Lithocholic acid, also known as 3α-hydroxy-5β-cholan-24-oic acid or LCA, is a bile acid that acts as a detergent to solubilize fats for absorption. Bacterial action in the colon produces LCA from chenodeoxycholic acid by reduction of the hydro ...
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 (or out), termed beta (β; often drawn by convention as a solid line), or down, termed alpha (α; displayed as a dashed line). All bile acids have a 3-hydroxyl group, derived from the parent molecule, cholesterol, in which the 3-hydroxyl is beta.
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 (CYP7A1) forming 7α-hydroxycholesterol
7α-Hydroxycholesterol is a precursor of bile acids, created by cholesterol 7α-hydroxylase (CYP7A1). Its formation is the rate-determining step
In chemical kinetics, the overall rate of a reaction is often approximately determined by the slowes ...
. 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 (A and B) 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
Chenodeoxycholic acid (CDCA; also known as chenodesoxycholic acid, chenocholic acid and 3α,7α-dihydroxy-5β-cholan-24-oic acid) is a bile acid. Salts of this carboxylic acid are called chenodeoxycholates. Chenodeoxycholic acid is one of the mai ...
. This bile acid was first isolated from the domestic goose
A domestic goose is a goose that humans have domesticated and kept for their meat, eggs, or down feathers. Domestic geese have been derived through selective breeding from the wild greylag goose (''Anser anser domesticus'') and swan goose (''Ans ...
, from which the "cheno" portion of the name was derived (Greek: χήν = goose). The 5β in 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, at the end of the side-chain. Chenodeoxycholic acid is made by many species, and is the prototypic functional bile acid.
An alternative (acidic) pathway of bile acid synthesis is initiated by mitochondrial sterol 27-hydroxylase (CYP27A1
CYP27A1 is a gene encoding a cytochrome P450 oxidase, and is commonly known as sterol 27-hydroxylase. This enzyme is located in many different tissues where it is found within the mitochondria. It is most prominently involved in the biosynthesi ...
), 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
A peroxisome () is a membrane-bound organelle, a type of microbody, found in the cytoplasm of virtually all eukaryotic cells. Peroxisomes are oxidative organelles. Frequently, molecular oxygen serves as a co-substrate, from which hydrogen per ...
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 (CYP7B1
25-hydroxycholesterol 7-alpha-hydroxylase also known as oxysterol and steroid 7-alpha-hydroxylase is an enzyme that in humans is encoded by the ''CYP7B1'' gene. This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochro ...
) generates oxysterols, which may be further converted in the liver to CDCA.
Cholic acid
Cholic acid, also known as 3α,7α,12α-trihydroxy-5β-cholan-24-oic acid is a primary bile acid that is insoluble in water (soluble in alcohol and acetic acid), it is a white crystalline substance. Salts of cholic acid are called cholates. Chol ...
, 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 (3α, 7α and 12α). In its synthesis in the liver, 12α hydroxylation is performed by the additional action of CYP8B1
CYP8B1 (cytochrome P450, family 8, subfamily B, polypeptide 1) also known as sterol 12-alpha-hydroxylase is a protein which in humans is encoded by the ''CYP8B1'' gene.
This gene encodes a member of the cytochrome P450 superfamily of enzymes. Th ...
. As this had already been described, the discovery of chenodeoxcholic acid (with 2 hydroxyl groups) made this new bile acid a "deoxycholic acid" in that it had one fewer hydroxyl group than cholic acid.
Deoxycholic acid
Deoxycholic acid 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 chenodeoxycholic acid. Bacteria ...
is formed from cholic acid by 7-dehydroxylation, resulting in 2 hydroxyl groups (3α and 12α). This process with chenodeoxycholic acid results in a bile acid with only a 3α hydroxyl group, termed lithocholic acid
Lithocholic acid, also known as 3α-hydroxy-5β-cholan-24-oic acid or LCA, is a bile acid that acts as a detergent to solubilize fats for absorption. Bacterial action in the colon produces LCA from chenodeoxycholic acid by reduction of the hydro ...
(litho = stone) 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 (including humans) utilize 12α for their third hydroxyl group position, producing cholic acid. In mice and other rodents, 6β hydroxylation forms muricholic acids (α or β depending on the 7 hydroxyl position). Pigs have 6α hydroxylation in hyocholic acid (3α,6α,7α-trihydroxy-5β-cholanoic 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
Ursodeoxycholic acid (UDCA), also known as ursodiol, is a secondary bile acid, produced in humans and most other species from metabolism by intestinal bacteria. It is synthesized in the liver in some species, and was first identified in bile of ...
was first isolated from bear bile
Bears are carnivoran mammals of the family Ursidae. They are classified as caniforms, or doglike carnivorans. Although only eight species of bears are extant, they are widespread, appearing in a wide variety of habitats throughout the Nor ...
, which has been used medicinally for centuries. Its structure resembles chenodeoxycholic acid but with the 7-hydroxyl group in the β position.
Obeticholic acid
Obeticholic acid (OCA), sold under the brand name Ocaliva, is a semi-synthetic bile acid analogue which has the chemical structure 6α-ethyl-chenodeoxycholic acid. It is used as a medication used to treat primary biliary cholangitis. Intercept ...
, 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.
Hormonal actions
Bile acids also act as steroid hormones, secreted from the liver, absorbed from the intestine and having various direct metabolic actions in the body through the nuclear receptor Farnesoid X receptor (FXR), also known by its gene name . Another bile acid receptor is the cell membrane receptor known as G protein-coupled bile acid receptor
The G protein-coupled bile acid receptor 1 (GPBAR1) also known G-protein coupled receptor 19 (GPCR19), membrane-type receptor for bile acids (M-BAR) or TGR5 as is a protein that in humans is encoded by the ''GPBAR1'' gene.
Function
This gene ...
1 or TGR5. Many of their functions as signaling molecules in the liver and the intestines are by activating FXR, whereas TGR5 may be involved in metabolic, endocrine and neurological functions.
Regulation of synthesis
As surfactants or detergents, bile acids are potentially toxic to cells, and so their concentration
In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', ''molar concentration'', ''number concentration'', an ...
s are tightly regulated. Activation of FXR in the liver inhibits synthesis of bile acids, and is one mechanism of feedback control when bile acid levels are too high. Secondly, FXR activation by bile acids during absorption in the intestine increases transcription and synthesis of FGF19
Fibroblast growth factor 19 is a protein that in humans is encoded by the ''FGF19'' gene. It functions as a hormone, regulating bile acid synthesis, with effects on glucose and lipid metabolism. Reduced synthesis, and blood levels, may be a factor ...
, which then inhibits bile acid synthesis in the liver.
Metabolic functions
Emerging evidence associates FXR activation with alterations in triglyceride
A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''wikt:tri-#Prefix, tri-'' and ''glyceride'').
Triglycerides are the main constituents of body fat in humans and other ...
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
, glucose metabolism
Carbohydrate metabolism is the whole of the biochemical processes responsible for the metabolic formation, breakdown, and interconversion of carbohydrates in living organisms.
Carbohydrates are central to many essential metabolic pathways. Pla ...
, and liver growth.
Other interactions
Bile acids bind to some other proteins in addition to their hormone receptors (FXR and TGR5) and their transporters. Among these protein targets, the enzyme N-acyl phosphatidylethanolamine-specific phospholipase D
N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) is an enzyme that catalyzes the release of N-acylethanolamine (NAE) from N-acyl-phosphatidylethanolamine (NAPE). This is a major part of the process that converts ordinary lipids into ch ...
(NAPE-PLD) generates bioactive lipid amides (e.g. the endogenous cannabinoid
Cannabinoids () are several structural classes of compounds found in the cannabis plant primarily and most animal organisms (although insects lack such receptors) or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tet ...
anandamide
Anandamide (ANA), also known as ''N''-arachidonoylethanolamine (AEA), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid rec ...
) that play important roles in several physiological pathways including stress and pain responses, appetite, and lifespan. NAPE-PLD NAPE-PLD may refer to:
* N-acyl phosphatidylethanolamine-specific phospholipase D, an enzyme
* N-acetylphosphatidylethanolamine-hydrolysing phospholipase D, an enzyme
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