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.
Factors That Activate Retinoid X Receptors
- 9-cis retinoic acid [R]
- Synthetic retinoids/rexinoids (HX630, LG268, LG101506, LGD1069, etc.) [R, R]
- Honokiol [R]
- Green tea increases RXR levels [R]
RXRs Help with Immune System Function
Retinoid X Receptors (RXRs) are vital for the control of genes that are involved in the immune response [R].
1) RXR Activation Helps with Autoimmunity
RXR Activation 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 [R].
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 [R].
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 [R].
RXRs Work with RARs to Reduce 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 [R, R].
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 [R].
RXRs Work with RARs to Help 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 [R].
Activation of pathways involving the retinoid x receptors promote the development of a healthy intestinal barrier, which reduces the risk of leaky gut [R].
2) RXRs Are Needed for Healthy Inflammatory Responses
Retinoid X receptors (RXRs) are important for the control of genes that are involved in the immune response to inflammation [R].
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 [R].
RXRs are potential targets for immunotherapy during chronic inflammatory diseases [R].
3) Retinoid X Receptors and Cancer
Proper retinoid X receptor transmission prevents cancer. The retinoic x receptors have been identified as possible targets for cancer therapy and treatment [R].
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 [R].
Green tea polyphenols activate RXR-α.
Laboratory animals with colon cancer have a lower RXR-α production. Increasing RXR levels by green tea polyphenols helped reduce the risk of colon cancer in these animals [R].
Retinoid X Receptors Help with Energy Production
4) Retinoid X Receptors Help Prevent Obesity
The retinoid X receptors are involved in metabolic transmission pathways that reduce the risk of obesity when properly activated [R].
Laboratory animals without RXR-α in their livers eat less, but weigh more compared to healthy animals [R].
5) Retinoid X Receptor Activation Reduces Cholesterol Levels
Laboratory animals without RXR-α in their livers have higher cholesterol levels and are prone to fatty liver [R].
Both of these defects are key risk factors for obesity [R].
6) Retinoid X Receptor Activation 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 [R].
In cell-based studies, molecules that activated retinoid X receptors also prevented oxidative damage from high blood sugar [R].
7) RXRs Help Prevent Vascular Diseases
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 [R].
By preventing inflammation in muscle cells, RXR activators prevent blood vessel disorders [R].
RXRs and Development
8) RXRs Help Maintain Healthy Skin
9) Retinoid X Receptor Signalling Is Vital for 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 [R].
RXR-α is especially important in promoting gene production (cellular production) associated with early-life development; additionally, a fetus cannot develop properly without sufficient transmission from this receptor [R, R].
Laboratory animals without the RXR-α also cannot develop healthy eyes and vision [R].
In most cases, these animals also fail to thrive during early development [R].
Laboratory animals without the RXR-β and RXR-γ genes have metabolic and behavioral defects [R].
RXRs and the Nervous System
10) RXRs and RARS Are Important for Brain and Synaptic Plasticity
However, in mice, excessive levels of vitamin A also result in cognitive deficits and reduced cell growth in the hippocampus [R].
11) RXRs, RARs, and Neurotransmitters
RXRs and RARs are important for the cellular production of [R]:
Neurotransmitters and Their Receptors
- Dopamine [R]
- Oxytocin [R]
- Dopamine D2 receptors [R]
- Serotonin [R]
- Glutamate receptors [R]
- Delta-opioid receptors [R]
- Nicotinic acetylcholine receptors [R]
- GABA type A receptors [R]
Enzymes that are involved in the production, conversion, or breakdowns of neurotransmitters:
- Tyrosine hydroxylase, an enzyme that helps stimulate neurotransmitters (dopamine, epinephrine, norepinephrine) [R]
- Dopamine β-hydroxylase converts dopamine into norepinephrine [R]
Retinoid X Receptors Bind to Other Vitamins and Hormone Receptors
1) Retinoid X Receptors Partner with Retinoic Acid Receptors (RARs)
2) RXRs Work with 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 [R].
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 [R].
3) RXRs Work with Vitamin D Receptors (VDR)
RXRs increase gene-activating effects of vitamin D on certain genes [R].
RXRγ and VDR also work together to guarantee the proper functioning of nerve cells [R].
Decreased VDR function results in symptoms of low vitamin D levels. This causes muscle weakness, among other health problems [R].
On the other hand, excess VDR production in mice bone cells prevented bone loss during vitamin D deficiency [R].
4) RXRs and the Liver X Receptor (LXR)
Liver X receptors [R]:
- 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 [R].
5) RXRs and Peroxisome-Proliferator-Activated Receptors (PPAR)
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 [R].
6) RXRs and the 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 [R].
- 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
7) RXR Works with the Pregnane X Receptor and the Constitutive Androstane Receptor
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 [R].
Both PXR and CAR are responsible for the transportation of substances (drugs and steroids) out of the body [R].
8) Other Receptors That Work with RXRs
RXRs form heterodimers with the following nuclear receptors [R]:
- Small heterodimer partner (SHP)/NR0B2
- Photoreceptor cell-specific nuclear receptor (PNR)/NR2E3
- ErbA-related protein 2 (EAR2)/NR2F6
- Nerve growth factor-induced gene B (NUR77)/NR4A1
- Nuclear receptor related 1 protein (NURR1)/NR4A2
RXR Gene Mutations and Dysfunctions
1) Developmental Defects Caused By RXR-α Null-Mutations
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 [R]
- Failure of uterus and vagina development [R]
- Kidney malformation
- Bone and tissue malformation [R]
- Retina defects [R]
2) RXR Mutations Lead to 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 [R].
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 [R].
3) Retinoid X Receptor Dysfunction May Cause 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 [R].
Retinoid toxicity and deficiency causes symptoms similar to those caused by schizophrenia [R].
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 [R].
4) RXR-α Loss Affects Alcohol Metabolism
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 [R].
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 [R].
5) RXR-β Mutation Causes Infertility
Additionally, the surviving male mice had abnormal sperm formation. This caused all of them to be sterile and unable to reproduce [R].
Side Effects of RXR Activators (Agonists)
Synthetic RXR activators (agonists) have side effects, such as cholesterol elevation and hypothyroidism [R].
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 [R].
Technicals: Types of Retinoid X Receptors
- 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 [R]
Each RXR subtype is encoded by different genes, and interacts with different biological pathways when activated [R].
In most tissues, RXR-α takes over during the loss of RXR-γ function [R].
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