The liver X receptor (LXR) is a member of the
nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the ex ...
family of
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
s and is closely related to nuclear receptors such as the
PPARs,
FXR and
RXR. Liver X receptors (LXRs) are important regulators of
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
,
fatty acid
In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...
, and
glucose
Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
homeostasis
In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
. LXRs were earlier classified as
orphan
An orphan is a child whose parents have died, are unknown, or have permanently abandoned them. It can also refer to a child who has lost only one parent, as the Hebrew language, Hebrew translation, for example, is "fatherless". In some languages ...
nuclear receptors, however, upon discovery of endogenous
oxysterol
An oxysterol is a derivative of cholesterol obtained by Redox, oxidation involving enzymes and / or pro-oxidants. Such compounds play important roles in various biological processes such as cholesterol homeostasis, lipid metabolism (sphingolipids, ...
s as ligands they were subsequently deorphanized.
Two
isoforms
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
of LXR have been identified and are referred to as
LXRα and
LXRβ. The liver X receptors are classified into subfamily 1 (
thyroid hormone receptor-like) of the
nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the ex ...
superfamily, and are given the nuclear receptor nomenclature symbols NR1H3 (LXRα) and NR1H2 (LXRβ) respectively.
LXRα and LXRβ were discovered separately between 1994-1995. LXRα isoform was independently identified by two groups and initially named RLD-1
and LXR,
whereas four groups identified the LXRβ isoform and called it UR,
NER,
OR-1,
and RIP-15.
The human LXRα
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
is located on
chromosome 11p11.2, while the LXRβ
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
is located on
chromosome 19
Chromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 61.7 million base pairs, the building material of DNA. It is considered the most Gene density, gene-ri ...
q13.3.
Expression
While the expression of LXRα and LXRβ in various
tissues overlap the tissue distribution pattern of these two isoforms differ considerably. LXRα expression is restricted to
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
,
kidney
In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
,
intestine
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. T ...
,
fat
In nutrition science, nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such chemical compound, compounds, most commonly those that occur in living beings or in food.
The term often refers specif ...
tissue,
macrophages
Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
,
lung
The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...
, and
spleen
The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter.
The spleen plays important roles in reg ...
and is highest in
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
, hence the name liver X receptor α (LXRα). LXRβ is expressed in almost all
tissues and
organs hence the early name UR (ubiquitous receptor).
The different pattern of expression suggests that LXRα and LXRβ have different roles in regulating physiological function.
Structure
Crystal structure of human liver X receptor β (LXRβ) forms a heterodimer with its partner retinoid X receptor α (RXRα) on its cognate element an AGGTCA direct repeat spaced by 4 nucleotides showing an extended X-shaped arrangement with DNA- and ligand-binding domains crossed. In contrast, the parallel domain arrangement of other NRs bind an AGGTCA direct repeat spaced by 1 nucleotide. The LXRβ core binds DNA via canonical contacts and auxiliary DNA contacts that enhance affinity for the response element.

Crystal structure of human liver X receptor α (LXRα) also forms a heterodimer with its partner retinoid X receptor β (RXRβ). The LXRα-RXRβ heterodimer (PDB 1UHL) binds synthetic LXR oxysterol agonist T-0901317. The ligand-binding pocket predominantly consists of hydrophobic residues. The most critical residues to the binding pocket include E267, R305, H421, and W443. The binding pocket accommodates oxysterols of molecular volumes up to 400 Å
3 and T-0901317 easily positions itself with a molecular volume of 304 Å
3. H421 forms a hydrogen bond with T-0901317's hydroxyl head group which lowers the pKa of the H421 imidazole side chain. As a result, the imidazole side chain interacts electrostatically with π-electrons of W443's indole side chain to stabilize the active conformation of the helices.
The phenyl group of T-0901317 extends toward the β-sheet side of the binding pocket and partially occupies it. The unoccupied section contains hydrophilic, polar residues E267 and R305. H421 and W443 anchor the 22-, 24-, or 27-hydroxyl group of an oxysterol to the binding pocket via hydrogen bonding and electrostatic interactions. The conformational flexibility of R305 allows it to bind the 3-hydroxyl group and stabilize an oxysterol.
Activation/ligands
LXRα and LXRβ form
heterodimer
In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ...
s with the obligate partner
retinoid X receptor
The retinoid X receptor (RXR) is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9-''cis''-13,14-dihydroretinoic acid, which may be an endogenous mamma ...
(
RXR), which is activated by 9-cis-13,14-dihydroretinoic acid.
The LXR/RXR heterodimer can be activated with either an LXR
agonist
An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
(oxysterols) or a RXR
agonist
An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
(9-cis-13,14-dihydroretinoic acid). Oxysterols, the oxygenated derivatives of
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
, such as
22(R)-hydroxycholesterol,
24(S)-hydroxycholesterol,
27-hydroxycholesterol, and
cholestenoic acid, are the natural
ligand
In coordination chemistry, a ligand is an ion or molecule with a 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 el ...
s for LXR.
After activation, LXR binds to LXR response element (LXRE), usually a variant of the idealized
sequence
In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is cal ...
AGGTCAN4AGGTCA, in the
promoters of LXRs' target
genes
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. Some synthetic LXR
agonists
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agon ...
have been developed, including non
steroid
A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration.
Steroids have two principal biological functions: as important components of cell membranes t ...
al LXR agonists T0901317
and GW3965.
The hexacyclic aromatic ketones, (-)anthrabenzoxocinone and (-)bischloroanthrabenzoxocinone ((-)-BABX) derived from a ''Streptomyces sp.'' have micromolar affinity for LXR-α.
LXR-623 (
WAY 252623) CAS:
75787-07-8
Target genes
LXR-RXR nuclear receptor heterodimers function as transcriptional regulators for genes involved in lipid metabolism, lipid homeostasis, and inflammation.
Target
genes
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
of LXRs are involved in
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
and
lipid
Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...
metabolism
Metabolism (, from ''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 cellular processes; the co ...
regulation,
including:
*
ABC – ATP Binding Cassette transporter isoforms
A1,
G1,
G5, and
G8
*
ApoE
Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene ''APOE''.
Apo-E belongs to a family ...
– Apolipoprotein E
*
CETP – CholEsterylester Transfer Protein
*
FAS – Fatty Acid Synthase
*
CYP7A1 – CYtochrome P450 isoform 7A1 - cholesterol 7α-hydroxylase
*
LPL – LipoProtein Lipase
*
LXR-α – Liver X Receptor-α (a somewhat unusual example of receptor up-regulating its own expression)
*
SREBP-1c – Sterol Regulatory Element Binding Protein 1c
*
ChREBP – Carbohydrate Regulatory Element Binding Protein
Role in metabolism
The importance of LXRs in physiological
lipid
Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...
and
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
metabolism
Metabolism (, from ''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 cellular processes; the co ...
suggests that they may influence the development of metabolic disorders such as
hyperlipidemia
Hyperlipidemia is abnormally high levels of any or all lipids (e.g. fats, triglycerides, cholesterol, phospholipids) or lipoproteins in the blood. citing: and The term ''hyperlipidemia'' refers to the laboratory finding itself and is also use ...
and
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
. Evidence for this idea has been observed by recent studies that linked LXR activity to the pathogenesis of atherosclerosis. LXRα
knockout mice
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
are healthy when fed with a low-
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
diet. However, LXRα
knockout mice
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
develop enlarged fatty
livers, degeneration of
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
cells, high
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
levels in
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
, and impaired
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
function when fed a high-
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
diet.
LXRβ
knockout mice
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
are unaffected by a high-
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
diet, suggesting that LXRα and LXRβ have separate roles. LXRs regulate
fatty acid
In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...
synthesis by modulating the expression of
sterol regulatory element binding protein-1c (SREBP-1c).
LXRs also regulate
lipid
Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...
homeostasis
In biology, homeostasis (British English, British also homoeostasis; ) is the state of steady internal physics, physical and chemistry, chemical conditions maintained by organism, living systems. This is the condition of optimal functioning fo ...
in the
brain
The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
. LXRα and LXRβ double
knockout mice
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
develop neurodegenerative changes in
brain
The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...
tissue.
LXRβ
knockout mice
A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...
results in adult-onset
motor neuron
A motor neuron (or motoneuron), also known as efferent neuron is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly o ...
degeneration in male mice.
Adiponectin induces
ABCA1-mediated
reverse cholesterol transport by activation of
PPAR-γ and LXRα/β.
Potential therapeutic applications of LXR agonists
LXR
agonists
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agon ...
are effective for treatment of murine models of
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
,
diabetes
Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
, anti-
inflammation
Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
,
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
, and cancer.
Cardiovascular
Treatment with LXR
agonist
An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
s (hypocholamide, T0901317, GW3965, or N,N-dimethyl-3beta-hydroxy-cholenamide (DMHCA)) lowers the
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
level in
serum and
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
and inhibits the development of
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
in murine disease models.
Synthetic LXR
agonist
An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
GW3965 improves
glucose
Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
tolerance in a murine model of diet-induced
obesity
Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...
and
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
resistance by regulating
genes
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
involved in
glucose
Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...
metabolism in
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
and
adipose
Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, Blood vessel, vascular endothel ...
tissue.
GW3965 inhibits the expression of inflammatory mediators in cultured
macrophage
Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
and
inflammation
Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
in mice.
Aberrant LXR signaling in
macrophage
Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...
s due to the
oxidized
Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...
cholesterol
Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils.
Cholesterol is biosynthesis, biosynthesized by all anima ...
7-ketocholesterol promotes the inflammation that leads to
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
.
For this reason, 7-ketocholesterol is a therapeutic target for the prevention and treatment of atherosclerosis.
When lipogenesis is increased by pharmacological activation of the liver X receptor, hepatic VLDL production is increased 2.5-fold, and the liver produces large TG-rich VLDL particles. Glucose induces expression of LXR target genes involved in cholesterol homeostasis like
ABCA1 which is defective in
Tangier disease. A common feature of many metabolic pathways is their control by
retinoid X receptor
The retinoid X receptor (RXR) is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9-''cis''-13,14-dihydroretinoic acid, which may be an endogenous mamma ...
(RXR) heterodimers. LXR heterodimerises with RXR. Promiscuous RXR also heterodimerises with PPAR members.
PPAR-α plays a pivotal role in fatty acid catabolism in liver by upregulating the expression of numerous genes involved in mitochondrial fatty acid oxidation. Thus RXR is a common partner of two nuclear receptors acting in opposite directions with regard to fatty acid metabolism. So both LXR and PPAR-α compete for the limited pool of RXR and this dynamic equilibrium determines the direction of lipid metabolism.
Developing new potent and effective LXR
agonist
An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
s without the undesirable side effects may be beneficial for clinical usage.
In this regard, DMHCA was reported to reduce atherosclerosis in apolipoprotein E-deficient mice without inducing hypertriglyceridemia and liver steatosis.
Alzheimer's disease
Treatment with T0901317 decreases amyloidal beta production in an
Alzheimer's disease
Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
mouse model.
However, both T0901317 and GW3965 have been reported to increase
plasma and
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
triglycerides
A triglyceride (from ''wikt:tri-#Prefix, tri-'' and ''glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids.
Triglycerides are the main constituents of body fat in humans and oth ...
in some mice models, indicating that T0901317 and GW3965 may not be a good candidate for a therapeutic agent.
Cancer
LXR agonists (T0901317, 22(R)-hydroxycholesterol, and 24(S)-hydroxycholesterol) were also shown to suppress the proliferation of
prostate cancer
Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
and
breast cancer
Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
cells
as well as delay progression of
prostate cancer
Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
from
androgen
An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
-dependent status to
androgen
An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...
-independent status.
References
External links
*
(Nuclear Receptor Resource).
{{FXR and LXR modulators
Nuclear receptors, 1