The bile acid receptor (BAR), also known as farnesoid X receptor (FXR) or NR1H4 (nuclear receptor subfamily 1, group H, member 4), is a
nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroid hormone, steroids, thyroid hormone, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to ...
that is encoded by the ''NR1H4'' gene in humans.
Function
FXR is expressed at high levels in the liver and intestine.
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 ...
and other
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. Bile acids are conjugated with taurine or glycine residues to give anions called bile salts.
Primar ...
s are natural
ligands
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
for FXR. Similar to other nuclear receptors, when activated, FXR translocates to the
cell nucleus
The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...
, forms a
dimer
Dimer may refer to:
* Dimer (chemistry), a chemical structure formed from two similar sub-units
** Protein dimer, a protein quaternary structure
** d-dimer
* Dimer model, an item in statistical mechanics, based on ''domino tiling''
* Julius Dimer ( ...
(in this case a heterodimer with
RXR) and binds to
hormone response element Response elements are short sequences of DNA within a gene promoter or enhancer region that are able to bind specific transcription factors and regulate transcription of genes.
Under conditions of stress, a transcription activator protein bin ...
s on DNA, which up- or down-regulates the expression of certain
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s.
One of the primary functions of FXR activation is the suppression of
cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis from
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 memb ...
. FXR does not directly bind to the CYP7A1 promoter. Rather, FXR induces expression of
small heterodimer partner
The small heterodimer partner (SHP) also known as NR0B2 (nuclear receptor subfamily 0, group B, member 2) is a protein that in humans is encoded by the ''NR0B2'' gene. SHP is a member of the nuclear receptor family of intracellular transcription ...
(SHP), which then functions to inhibit transcription of the CYP7A1 gene. In this way, a
negative feedback
Negative feedback (or balancing feedback) occurs when some function of the output of a system, process, or mechanism is fed back in a manner that tends to reduce the fluctuations in the output, whether caused by changes in the input or by othe ...
pathway is established in which synthesis of bile acids is inhibited when cellular levels are already high.
FXR has also been found to be important in regulation of hepatic
triglyceride
A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride'').
Triglycerides are the main constituents of body fat in humans and other vertebrates, as ...
levels.
Specifically, FXR activation suppresses
lipogenesis
In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride s ...
and promotes
free fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...
oxidation
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or ...
by
PPARα
Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1 (nuclear receptor subfamily 1, group C, member 1), is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the ''PPARA'' gene ...
activation.
Studies have also shown the FXR to regulate the expression and activity of epithelial transport proteins involved in fluid homeostasis in the intestine, such as the
cystic fibrosis transmembrane conductance regulator
Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene.
Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked wi ...
(CFTR).
Activation of FXR in diabetic mice reduces plasma glucose and improves
insulin sensitivity
Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin.
Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood glucose (blood sugar) ...
, whereas inactivation of FXR has the opposite effect.
Interactions
Farnesoid X receptor has been shown to
interact
Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...
with:
*
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha and
*
Retinoid X receptor alpha.
Ligands
A number of ligands for FXR are known, of both natural and synthetic origin.
;Agonists
*
Cafestol
Cafestol is a diterpenoid molecule present in coffee beans. It is one of the compounds that may be responsible for proposed biological and pharmacological effects of coffee.
Sources
A typical bean of ''Coffea arabica'' contains about 0.4-0.7 ...
*
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 ...
*
Fexaramine
Fexaramine is an investigational compound which acts as an agonist of the farnesoid X receptor (FXR), which is a bile acid-activated nuclear receptor that controls bile-acid synthesis, conjugation and transport, as well as lipid metabolism through ...
*
GW 4064
GW may refer to:
People
* George Washington, the first president of the United States
* Gene Wilder, American actor and comedian
Places
* Gawok railway station, a railway station in Indonesia (station code)
* George Washington Bridge across th ...
*
Ivermectin
Ivermectin (, '' EYE-vər-MEK-tin'') is an antiparasitic drug. After its discovery in 1975, its first uses were in veterinary medicine to prevent and treat heartworm and acariasis. Approved for human use in 1987, today it is used to treat i ...
*
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 ...
*
Tropifexor
Tropifexor is an investigational drug which acts as an agonist of the farnesoid X receptor (FXR). It was discovered by researchers from Novartis and Genomics Institute of the Novartis Research Foundation. Its synthesis and pharmacological propert ...
;Antagonists
*
Guggulsterone
Guggulsterone is a phytosteroid found in the resin of the guggul plant, ''Commiphora mukul''. Guggulsterone can exist as either of two stereoisomers, ''E''-guggulsterone and ''Z''-guggulsterone. In humans, it acts as an antagonist of the farneso ...
References
Further reading
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External links
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{{FXR and LXR modulators
g2
Transcription factors