Retinoid X receptors (RXRs) are vitamin A receptors that often partner with other important receptors, including retinoic acid receptors, vitamin D receptors, thyroid hormone receptors, and PPARs.
Therefore, these have critical roles in energy production (obesity, blood sugar, cholesterol), anti-inflammation, preventing leaky gut, skin health, and cancer prevention.
Could low vitamin A or low RXR activation contribute to your health problems? Read this post to learn more.
What Is a Retinoid X Receptor?
The retinoid X receptor (RXR) is a vitamin A receptor that often partners with other important receptors inside the cells. As a result, it has several important roles in energy production, immune responses, development and skin health.
Types of Retinoid X Receptors
There are three main sub-types of retinoid X receptors: RXR-α, RXR-β, and RXR-γ.
- RXR-α is found in the liver, lung, muscles, skin, kidney, and intestines
- RXR-β is found throughout the body
- RXR-γ is found in the brain, heart, and bone muscles [1]
Each RXR subtype is encoded by different genes and interacts with different biological pathways when activated [1].
Natural Activators of Retinoid X Receptors
RXRs Help with Immune System Function
Retinoid X Receptors (RXRs) are vital for the control of genes that are involved in the immune response [5].
1) Autoimmunity & Inflammation
Reduces Th1 and Increases Th2 Cells
Th1 and Th2 cell production influences the adaptive immune response. Th1 cells are mostly responsible for protecting against pathogens inside the cells. Meanwhile, Th2 cells protect against parasites that are located outside the cell [6].
The immune response’s outcome is controlled by changing the balance of Th1 and Th2 cells. RXR-α transmission normally suppresses the formation of Th1 cells and indirectly permits Th2 cell formation. Vitamin D receptors work with RXRs to inhibit Th1 and increase the Th2 response [6].
In a study of mice, scientists found that the RXR-α transmission pathway is necessary for Th2 responses. RXR-α deficiency decreases Th2 cell formation and causes Th1 cell levels to be too high [6].
Reduces Th17 and Increase Treg Cells
Th17 cell activation is linked to many autoimmune diseases, while Treg cells reduce autoimmunity. RXRs function with RARs to suppress Th17 cells. Activation of RXRs help inhibit Th17 cell growth and increase Treg cells [7, 8].
This RXR activation in CD4+ T cells (cells that could become either Th17 or Tregs) significantly ameliorated disease severity in mouse models of multiple sclerosis [7].
RXRs increase cAMP production in human skin tissue. This increases the level of immune cells in the skin and increases antimicrobial strength [9].
Helps Prevent Leaky Gut
Leaky gut is a condition where the tight junctions between the cells that line the gut have increased permeability. This means the gut content is exposed to the immune system, potentially causing inflammation [10].
Activation of pathways involving the retinoid x receptors promotes the development of a healthy intestinal barrier, which reduces the risk of a leaky gut [11].
Vitamin A supplementation in healthy children improved gut function, while vitamin A deficiency reduced intestinal barrier function [12].
Supports Healthy Inflammatory Responses
Retinoid X receptors (RXRs) are important for the control of genes that are involved in the immune response to inflammation [5].
In an animal model, mice that lack RXR-α in their myeloid cells had reduced CCL6 and CCL9 (proteins that attract, activate, and induce growth of immune cells) levels. This is evidence that RXR-α is needed for the transcription of these cytokines that respond to inflammation. The lack of RXR-α activation may prevent necessary inflammatory responses in the presence of injuries or infections [5].
RXRs are potential targets for immunotherapy during chronic inflammatory diseases [5].
2) Cancer
Proper retinoid X receptor transmission prevents cancer. The retinoic x receptors have been identified as possible targets for cancer therapy and treatment [13].
In cell studies, RXR-α interacts with other receptors to promote immune transmission that prevents the production of human breast cancer cells [14].
When scientists increased RXR-α in breast cancer cells, the cancer cells became more sensitive to RXR activators. This sensitivity made it easier for the activators to stop the cell growth cycle and stop cell production [14].
Green tea polyphenols activate RXR-α.
Laboratory animals with colon cancer have lower RXR-α production. Increasing RXR levels by green tea polyphenols helped reduce the risk of colon cancer in these animals [4].
DW22, an RXR-α agonist, arrests cell division and kills (induces apoptosis) cancer cells [15].
3) Helps Prevent Obesity
The retinoid X receptors are involved in metabolic transmission pathways that reduce the risk of obesity when properly activated [2].
Laboratory animals without RXR-α in their livers eat less but weigh more compared to healthy animals [2].
RXR-α is found in the liver where it maintains healthy fat metabolism [16].
In one study of diabetic rats, administration RXR activators increased their energy production [2].
On the other hand, the deletion of RXR-α in mice fat cells made them resistant to obesity induced by high-fat diet or chemicals [2].
4) Reduces Cholesterol Levels
Laboratory animals without RXR-α in their livers have higher cholesterol levels and are prone to fatty liver disease [16].
Both of these defects are key risk factors for obesity [16].
Retinoic X receptors also signal with the farnesoid X receptor to balance cholesterol levels in the body [1].
5) Decreases Insulin Resistance
New therapies that improve insulin sensitivity include molecules that partner with RXR as part of a complex with other receptors. These partners then increase the function of genes involved in insulin action, fat cell production, fat energy production, and inflammation [17].
For example, RXR partners with PPARγ. This improves blood glucose levels, blood fat levels, reduces insulin resistance, and prevents other heart disease risk factors [17].
Additionally, treatment of obese and diabetic mice by activating RXR helped improve glucose energy production [18].
RXRγ overproduction in mice resulted in activated glucose energy production genes [18].
In cell-based studies, molecules that activated retinoid X receptors also prevented oxidative damage from high blood sugar [19].
6) Helps Cardiovascular Health
Specific activators that increase RXR activity help prevent vascular diseases (diseases of blood vessel health, such as thrombosis, heart disease, hardening of the arteries) by promoting blood vessel health [20].
Angiotensin II transmission increases inflammatory cytokines and causes abnormal blood vessel growth. In rat cells, RXR reduces angiotensin II signaling [20].
By preventing inflammation in muscle cells, RXR activators prevent blood vessel disorders [20].
7) Helps Maintain Healthy Skin
Retinoid X Receptors are partly responsible for skin vitality and health. In skin cells, RXRs work with the vitamin D receptors to allow for vitamin D synthesis from the sun [21].
These receptors play a crucial part in decreasing the symptoms of chronic hand eczema through increasing vitamin A binding affinity [22].
Additionally, RXRs increase cAMP production in human skin tissue. This increases the immune cells in the skin and increases antimicrobial strength [9].
8) Fetal Development
Healthy retinoic X function in pregnant women promotes proper absorption of vitamin D. This allows normal immune cell production in the placenta and prevents the development of allergies or asthma in newborns [23].
RXR-α is especially important in promoting gene production associated with early-life development; additionally, a fetus cannot develop properly without sufficient transmission from this receptor [2, 24].
Laboratory animals without the RXR-α gene cannot develop healthy heart tissue [25].
Laboratory animals without the RXR-α also cannot develop healthy eyes and vision [25].
Meanwhile, laboratory animals without RXR-β are sterile [1].
In most cases, these animals also fail to thrive during early development [1].
Laboratory animals without the RXR-β and RXR-γ genes have metabolic and behavioral defects [2].
9) Brain and Synaptic Plasticity
RXRs and RARs are important for neuronal and synaptic plasticity in the hippocampus [26].
However, in mice, excessive levels of vitamin A also result in cognitive deficits and reduced cell growth in the hippocampus [27].
10) Neurotransmitters
RXRs and RARs are important for the cellular production of [28]:
Neurotransmitters and Their Receptors
- Dopamine [28]
- Oxytocin [29]
- Dopamine D2 receptors [30]
- Serotonin [31]
- Glutamate receptors [32]
- Delta-opioid receptors [32]
- Nicotinic acetylcholine receptors [33]
- GABA type A receptors [31]
Enzymes that are involved in the production, conversion, or breakdowns of neurotransmitters:
- Tyrosine hydroxylase, an enzyme that helps stimulate neurotransmitters (dopamine, epinephrine, norepinephrine) [34]
- Dopamine β-hydroxylase converts dopamine into norepinephrine [35]
Partner Receptors
1) Retinoic Acid Receptors (RARs)
RXRs partner with RARs to control gene production in response to vitamin A [2, 24].
2) Thyroid Hormone Receptors (TR)
Retinoid X receptors (RXRs) bind with thyroid hormone receptors (TR).
TR-RXR heterodimers are responsible for many physiological processes, including embryonic development, metabolic rate balance, heart functions, and digestion [1].
In mice, the loss of thyroid hormone receptor causes problems with the heart, ear, and eye development. It also negatively affected liver energy production and thyroid hormone levels [36].
3) Vitamin D Receptors (VDR)
RXRs bind to and work with vitamin D receptors (VDR] [1].
White blood cells, skin cells, the colon, pituitary gland, and ovaries have vitamin D receptors.
Vitamin D receptors control calcium and phosphate uptake, transport, and balance. They also help with cell production and the immune response [1].
RXRs increase gene-activating effects of vitamin D on certain genes [37].
RXRγ and VDR also work together to guarantee the proper functioning of nerve cells [38].
Decreased VDR function results in symptoms of low vitamin D levels. This causes muscle weakness, among other health problems [39].
On the other hand, excess VDR production in mice bone cells prevented bone loss during vitamin D deficiency [40].
4) Liver X Receptor (LXR)
RXR partners with both liver X receptor-α and LXR-β.
Liver X receptors [1]:
- Provide fat and cholesterol energy production
- Offer immune system function – many different white blood cells have LXRs
- Control inflammatory responses in macrophages
Mice with damaged LXR pathways have problems with fat cell production. These damages also cause problems with metabolism [41].
5) PPARs
RXRs partners with peroxisome-proliferator-activated receptors (PPARs). These partnerships allow the cell to sense and respond to fatty acid molecules. This helps with fat energy production [1].
The RXR and PPARα complex may potentially treat high cholesterol [1].
Mice without the RXR-α gene often have defects in the PPARd and PPARγ transmission pathways. This causes mice to die in the early embryonic stages [41].
6) Farnesoid X Receptor (FXR)
RXRs form heterodimers with the farnesoid X receptor (FXR). FXR acts as the sensor for bile acids. FXR increases cellular production from genes involved in the energy production of cholesterol and bile acids [1].
- Keep various bile acids in the body balanced
- Increase cellular production from genes that allow for the expulsion of bile acids from cells
- Control digestion, since bile acids are important signals for the digestive system
- Increase insulin sensitivity
Mice without the FXR gene have high cholesterol and bile acids in their blood [1].
7) PXR and CAR
The pregnane X receptor (PXR, or SXR) is another binding partner for RXR. PXR increases the production of detoxifying enzymes. In the liver, small intestine, and colon, PXR helps detoxify and clear foreign toxic substances and drugs from the body [1].
RXR also binds with the constitutive androstane receptor (CAR). CAR is another receptor that helps detoxify and protect against harmful molecules [1].
Both PXR and CAR are responsible for the transportation of substances (drugs and steroids) out of the body [1].
RXR Gene Mutations and Dysfunctions
RXR genes are important for embryonic development. The loss of RXR-α gene function in mice causes vitamin A deficiency and heart malformation. These lead to death during embryonic development [43].
1) Developmental Defects
Null mutations cause a certain gene to not be found. Mice without the RXR-α gene may have many growth and development defects, including the following:
- Heart and lung underdevelopment [24]
- Failure of uterus and vagina development [44]
- Kidney malformation
- Bone and tissue malformation [45]
- Retina defects [24]
2) Cancer Development
Single-nucleotide polymorphisms in the retinoid X receptor (RXR) also interfere with proper vitamin D absorption. These polymorphisms are significant risk factors for ovarian cancer in older women [46].
SNPs inside of RXR-alpha that have been implicated in increased cancer risks include [46, 47]:
- rs749759
- rs1805352
- rs3132297
- rs3132296
- rs3118529
- rs3118536
- rs7861779
Excessive exposure to the sun and ultraviolet radiation substantially reduced cellular production of RXRs in the skin of lab animals. This led to a functional vitamin A deficiency, which increases the risks of skin cancer. However, pre-treatment with retinoic acid mitigated this reduction of RXR cellular production [48].
3) Schizophrenia
Schizophrenia is a disorder that causes visual and auditory hallucinations, along with other symptoms. There has been increasing evidence that retinoid dysregulation is a factor in schizophrenia development [28].
Retinoid toxicity and deficiency cause symptoms similar to those caused by schizophrenia [28].
The RAR/RXR complex controls various schizophrenia candidate genes. They include dopamine and dopamine receptors, serotonin, glutamate receptors, and many others [28].
Mutant mice without both RAR and RXR genes (RAR-RXR double null mutants) have abnormal movements and irregular dopamine transmission [28].
All of this evidence supports the theory that RXR and RAR play important parts in preventing schizophrenia. Without these receptors, the brain does not function normally. Dysregulation of retinoic acid helps cause schizophrenia [28].
4) Alcohol Metabolism
Retinol and alcohol metabolism overlap with each other. Vitamin A deficiency and alcohol toxicity cause similar abnormalities during fetus development [49].
Mice without both the retinoic acid receptor and retinoid X receptor (RAR-RXR) in the liver are more susceptible to alcoholic liver disease [49].
The ADH protein converts ethanol to acetaldehyde, which accounts for most of the toxic effects of alcohol. The level of ADH1 expression influences the risk for alcohol-induced liver injury [49].
In mice, RXR-α deficiency increased ADH activity, which enhanced alcohol and acetaldehyde clearance in the blood and liver. This results in more serious liver injuries [49].
Also, mutations in RXRs along with the NR4A2 gene increase alcohol dependence in humans, causing alcoholism [50].
Deficiency in the production of RXR-α caused a reduction of S-adenosylmethionine (SAMe) and glutathione (GSH) levels, both of which are important for alcohol detoxification. It also resulted in a more serious alcohol-induced liver injury [49].
5) Infertility
In one study, scientists bred a group of mice that did not have RXR-β gene activity. Around 50% of mice without the gene died before or during birth [51].
Additionally, the surviving male mice had abnormal sperm formation. This caused all of them to be sterile and unable to reproduce [51].
Side Effects of RXR Activators (Agonists)
Synthetic RXR activators (agonists) have side effects, such as cholesterol elevation and hypothyroidism [52].
RXR agonist treatment may also increase the risk of viral infections. In mice, RXR activators caused RXR-α overproduction. This increased host susceptibility to viral infections [53].
