Optimizing Retinoic Acid Receptors (RARs) function can help you fix leaky gut, lose weight, fix insulin resistance and heal from autoimmune diseases. Read this post to learn about 13 positive and negative effects of RAR activation, and ways to improve them.

Contents

Introduction to Retinoic Acid Receptors (RARs)

https://doi.org/10.1146/annurev-immunol-041015-055427

https://doi.org/10.1146/annurev-immunol-041015-055427

Retinoic acid receptors (RARs) are receptors for specific forms of vitamin A, retinol, and retinoic acid (R, R).

These receptors are necessary for the body to properly sense and utilize those forms of vitamin A (R, R).  As a result, the many benefits of vitamin A cannot be obtained without proper retinoic acid receptor function.

The retinoic acid receptors consist of 3 specific variations called subtypes.  The three subtypes –  RAR-α, RAR-β, and RAR-γ – are encoded by separate genes (R). The different subtypes are also produced and used differently in different tissues (R).

RARs are important for embryonic development, organ generation, vision, immune functions, energy production, and fertility (R).

Activation of RARs can be helpful in the treatment of disorders including type 2 diabetes, high cholesterol, immune disorders, and various cancers (R, R, R).

Other Receptors that Partner with Retinoic Acid Receptors

RARs combine with a protein called RXR (retinoid X receptors) and other nuclear receptors (PPARs, vitamin D receptor, and thyroid hormone receptors) to balance cellular energy production (R). This explains why vitamin A is important for these other receptors, i.e. PPAR, vitamin D, and thyroid hormone receptors to function well.

Health Benefits of Retinoic Acid Receptor Activity

1) Retinoic Acid Receptor Activation Increases Metabolism

Retinoic acid is important for energy metabolism because it promotes energy usage, especially in fat cells (R). It helps activate the gene expression of cells involved in carbohydrate and fat metabolism (R).

RARs can increase lipolysis (the breakdown of fats) and help keep fat levels at a balance. Retinoic acid treatment in obese animals induces RAR production, which can lead to weight loss (R).

2) Retinoic Acid Receptor Activation Improves Insulin Sensitivity

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Retinoic acid and RAR (RAR) activity also improved insulin sensitivity and glucose tolerance in animal studies (R).

The improvements in glucose tolerance are likely explained by the retinoic acid receptor’s interactions with the cells that produce insulin, pancreatic β cells.  These cells need RAR activity to produce healthy levels of insulin. Without RAR activity, the animals had a lower blood insulin level and impaired glucose-stimulated insulin secretion (R, R). Without RARs, the balance of glucose is disturbed (R).

3) Retinoic Acid Receptor Activity Protects the Heart in Diabetics

Diabetes can be a risk factor for heart disease. High blood sugar can induce programmed cell death (apoptosis) of heart muscle cells. In addition to having anti-diabetic effects, RARs (RARs) and retinoid X receptors (RXRs) can help prevent diabetes-induced heart failure (R).

In rat heart muscle cells, all-trans retinoic acid activation of RARs and RXRs inhibited cell death. Specifically, RAR-α and RXR-α are required for maintaining heart cell survival (R).

4) Retinoic Acid Receptor-α Activation Increases HDL Cholesterol

The ABC transporter G1 (ABCG1) assists the body in balancing cholesterol levels. The removal of cholesterol helps prevent high cholesterol and maintain a healthy level of HDL (good) cholesterol) (R, R).

In laboratory studies of human cells, RAR-α activation increases ABCG1 production, which led to an increase in HDL cholesterol ejection from macrophages (a type of white blood cell) (R).

5) Retinoic Acid Receptor Activity Can Potentially Help Treat Alzheimer’s Disease

Alzheimer’s disease is characterized by memory loss and inflammation of the nervous system.

In a mouse model of Alzheimer’s disease, administration of retinoic acid and retinoid X receptor activators helped improve memory (R).

Chromosome region 12q13 (which contains RAR-γ) is associated with late-onset Alzheimer’s disease, and retinoic acid can reduce cellular production of genes involved in early-onset Alzheimer’s disease (R).

Because retinoic acid and its receptors are involved in a variety of pathways that affect Alzheimer’s disease, manipulation of these receptors shows promise a treatment for the disease (R).

A general review of studies on the retinoic acid receptors (RARs) determined that they facilitate learning and memory processes generally (R).

6) Retinoic Acid Receptor Expression Improves Sleep Quality

sleeping-beaut

RAR-β expression increases delta brain wave activity during slow-wave (deep) sleep. Delta wave activity stimulates the release of several hormones that assist in cellular growth and maintenance. Vitamin A deficiency and the lack of RAR-β expression reduces delta power and thus reduces deep sleep (R, R).

In animal studies, the administration of the retinoic acid receptor activator Am80 improved REM sleep. RAR activation can also slow the age-related decline of sleep quality (R).

7) Retinoic Acid Receptor Function is Essential for Male Fertility

Sperm formation requires the form of retinoic acid called all-trans retinoic acid (ATRA) (R).

In animal studies, RAR-α deficiency in males leads to sterility. Disruption of the RAR-α gene can also lead to poor testicular health and can inhibit sperm production (R, R).

8) Retinoic Acid Receptors and Skin Health

RARs and RXRs are abundantly present in abundance in the skin (R). Vitamin A, which activates the retinoic acid receptors, is important for the development and integrity of skin (R, R2).

Problems with the receptors RXR, RAR-α, and RAR-γ can cause inflammatory skin diseases and poor skin health (R).

Abnormal metabolism of vitamin A can contribute to psoriasis, ichthyosis, and eczema (R, R2, R3).

Synthetic vitamin A forms, such as tretinoin and isotretinoin, have been developed and used for the treatment of acne and skin aging (R, R2, R3).

9) Retinoic Acid Receptors are Critical for Growth and Development

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Retinoic acid receptors (RARs) are important for development, and RAR deficiency can cause developmental defects.

Animal studies show that mice without the RAR-α, RAR-β, or RAR-γ genes usually die before or during birth because of developmental defects (R).

All three RAR genes function in mouse brains during later development in embryos and newborns. Studies indicate that RARs are vital for motor function, learning, and memory. Retinoic acid is also required for nerve cell formation in the spinal cord (R).

Embryonic eye development requires RAR activity, and RAR-β absence causes impaired vision in animal studies (R).

Additionally, embryonic inner ear development requires RAR-α and RAR-γ. Animals without RAR-α expression exhibit hearing deficiency related to middle ear function, supporting the receptor’s importance for hearing (R).

Animals without RAR-γ exhibit growth deficiency. RAR-γ removal is associated with a lower gene expression of factors that are vital for joint formation (R).

In animals, decreased expression of RAR-γ leads to birth defects and growth deficiency and can also cause bone and blood vessel defects (R).

Additionally, the suppression of RARs due to vitamin A deficiency and diabetes can also contribute to skeleton underdevelopment in mouse embryos (R).

RAR-γ plays a critical role in the creation of new blood cells (hematopoiesis).  Animal studies also show that RARs help to maintain the balance between the regeneration of blood originating cells and their production (R).

RAR-γ also helps maintain stem cell production (R).

RARs are also needed in the growth and development of important organs, such as the heart, lungs, and digestive tracts. Without RARs, tissues and organs do not develop correctly (R).

10) Retinoic Acid Receptors Support the Immune System

Retinoic acid and its receptors (RARs and RXRs) play important roles in the immune system. They play a part in immune cells production and the immune response.

Retinoids and the receptors help in the development of lymphoid organs, which are part of the immune system and help defend the body against pathogens (R).

RAR activation and retinoic acid activity control the development and functions of various immune cells (R).

RAR receptor activation is important for the production of T-cells, including (R):

Additionally, retinoic acid and RAR activity suppress inflammation (R).

Retinoic acid itself, as well as expression of the receptors RAR-α and RAR-β, promote Th2 dominance and suppress Th1 cytokines (R).

Deficiencies of retinoic acids can decrease immune function (R).

11) Retinoic Acid Receptors Can Help Prevent Leaky Gut

increased_intestinal_permeability

Leaky gut, also called intestinal permeability, is a condition where the gut lining has an increased permeability. This exposes microbes, toxins, and food particles to the immune system where they produce inflammation. Leaky gut is associated with several autoimmune diseases, allergies, and other inflammatory health problems (R).

RAR-α helps maintain barrier function and helped reduce the breakdown of the intestinal barrier in cell-based studies (R).

Retinoic acid acts via the retinoic acid receptors (RARs) and retinoid X receptors (RXRs) to help gut tissues to develop.Intercellular tight junctions help keep the intestinal epithelial barrier in place. RAR activation is important for tight junctions between cells in the gut to form correctly (R). Therefore, vitamin A supplementation can improve gut barrier integrity (R) and Vitamin A deficiency hampers gut barrier function (R). Additionally, retinoic acid depletion leads to the disruption of functional tight junctions, another factor that increases gut permeability (R).

12) Retinoic Acid Receptor Activation May Treat Multiple Sclerosis

In animal studies, all-trans retinoic acid (ATRA, an activator of RARs) was able to reduce the severity of experimental autoimmune encephalomyelitis, which is an animal model of multiple sclerosis (R).

In animal studies, ATRA and Am80 (synthetic RAR-α and RAR-β activators) suppressed inflammation in optic nerve fibers. The activation of the RARs helped reduce eye inflammation and protected the optic nerve. This neuroprotective and anti-inflammatory effects of RAR activators suggest that RAR activation may potentially help treat multiple sclerosis in humans (R).

13) Retinoic Acid Receptors and Cancer

By changing gene expression, RARs can inhibit the growth of many types of tumor cells (R, R). However, the roles of RARs in cancer are mixed. RAR expression seems to stimulate cancer growth in some cases while inhibiting it in others.

Lung Cancer

There is conflicting evidence on the retinoic acid receptor’s role in lung cancer.

The loss of RAR-β occurs in lung cancer cell lines. Scientists think that defective retinoid receptor expression might be involved in lung cancer (R).

In studies of human lung cancer cell lines, the activation of RARs and RXRs contribute to the induction of the RAR-β gene. Then, RAR-β expression leads to growth inhibition and apoptosis (programmed cell death) of the cancer cells by retinoids (R).

RAR-β2 is associated with fewer lung tumors in animals. Scientists thought that RAR-β might function as a tumor suppressor gene (R, R).

However, in a study of 595 patients with non-small-cell-lung cancer (NSCLC), RAR-β gene expression is associated with a poor prognosis. This result conflicts with previous research that RAR-β can help suppress lung tumors (R).

Two hypotheses might be able to explain these conflicting results. One hypothesis is that, in lung cancer, RAR-β might be inactive and cannot suppress tumors. The other hypothesis is that an increase in RAR-β4 might enhance cancer growth (R).

RAR-β may play a double role and affects both tumor suppression and tumor promotion (R).

Breast Cancer

Around 70% of breast cancer cells have the estrogen receptor-α (ER-α) nuclear receptor. RAR-α is an estrogen target gene. Estrogen-mediated transcription and cell proliferation require RAR-α (R).

RAR-α plays an essential role in activating estrogen-mediated gene expression and can help with estrogen treatments of breast cancer. In a study of 263 breast cancer patients with ER-α, the presence of the RAR-α gene was associated with positive clinical outcomes (R).

Although its mechanisms are unclear, RAR-α, and ER-α can work together to help treat breast cancer (R).

Additionally, the loss of RAR-β expression occurs early in the formation of breast cancer cells.  Even though its mechanism is unknown, RAR-β seems to play a part in breast tumor suppression (R).

Stomach Cancer

In stomach cancer cells, the RAR-α and RAR-β genes have lower levels of expression in stomach cancer tissue as compared to normal tissue (R, R).

Higher levels of RAR-α expression in stomach cancer cells is associated with a positive prognostic factor for survival. RAR-α expression positively correlates with the responsiveness to all-trans-retinoic acid therapy. This indicates that retinoids may show promise in the treatment of stomach cancer (R).

Oral Cancer

RAR-β expression in oral cancer cells is associated with a better response to cancer treatment. While it may be a marker for the prevention of oral cancer, it does not directly influence the cancer cells (R).

However, the overexpression of RAR-α in the cells of oral cancer patients is associated with a poor prognosis (R).

Other Cancers

The loss of RAR-γ expression in skin cells is associated with skin cancer (R).

In cervical cancer cell lines, RAR-β can potentially lower the production of oncogenes (genes that can turn normal cells into cancer cells) (R).

Mutations in the RAR-α gene is associated with leukemia (R).

Retinoic Acid Receptors: The Bad

1) Retinoic Acid Receptors May Contribute to Skin Aging

The receptors RAR-α, and RAR-γ are produced in large amounts in skin cells. Skin development requires these receptors (R).

However, the production of RAR-α may play a role in skin aging. In human skin cells, a significant increase of RAR-α was associated with aged skin. This increase of RAR-α expression results in the overproduction of MMP-1 (R).

MMP-1 is an enzyme that degrades the extracellular matrix of skin cells. The extracellular matrix provides the structure and support for these cells. When MMP-1 degrades the extracellular matrix, it contributes to skin aging (R).

2) Retinoic Acid Receptor-α Might Induce Inflammation in Some Cases

Inflammatory cells express RARs (RARs). RAR-α can induce inflammation. Rheumatoid arthritis therapy can potentially target these receptors (R).

In a study of cells from rheumatoid arthritis and osteoarthritis patients, RAR-α increases IL-2 secretion, which can induce inflammation. Additionally, in animal models of arthritis, drugs that reduced RAR activity helped block the progression of arthritis (R).

Thus, RAR-α might play a role in inflammation and joint destruction in arthritis (R).

3) Retinoic Acid Receptor Activation May Promote Alcohol-Induced Cognitive Decline

While RARs and RXRs are important for brain function. Alcohol consumption shifts vitamin A metabolism towards having excessive RAR and vitamin A levels in the nervous system (R). This may be caused by alcohol’s damage to the liver, which is where the body stores vitamin A.

In an animal model of chronic alcohol consumption, blocking RAR-β with the drug CD2665 mitigate the cognitive decline associated with the alcohol consumption (R).

Retinoic Acid Receptor Activators

How to Naturally Activate Retinoic Acid Receptors

Retinoic acid is a form of Vitamin A. All-trans retinoic acid and 9-cis-retinoic acids activate RARs (RARs) (R).

Carotenoids (α-carotene, β-carotene, and β-cryptoxanthin) can convert into retinoids (Vitamin A) (R).

However, not all carotenoids can increase RAR activity without being converted to retinoids. β-carotene does not significantly activate RARs when compared to all-trans retinoic acid (R).

Retinoic Acid Receptor Inhibitors

Antagonists (drugs that inhibit RAR action)

  • LG100815 (R)
  • Ro 41-5253 (R)
  • BMS-189453 (R)
  • BMS-189532 (R)
  • BMS-195614 (R)
  • AGN 193109 (R)
  • AGN194310 (R)
  • AGN194431 (R)
  • CD 2665 (R)
  • ER 50891 (R)
  • LE 135 (R)
  • LE 540 (R)
  • MM 11253 (R)

Technical: Retinoic Acid Receptor Interactions with Other Transcription Factors

Nuclear receptors, also known as transcription factors, are proteins that can sense steroid and thyroid hormones. When activated, they work with other proteins to either increase or decrease cellular production, aiding growth and development (R).

1) Retinoic Acid Receptors and Retinoid X Receptors

RARs (RARs) and retinoid X receptors (RXRs) can form protein complexes (heterodimers) with each other. They work together to control the transcription of target genes (R).

Without RXR expression, many problems can occur during development. Mutations in RXR can cause metabolic and behavioral defects, as well as death due to heart defects. However, the deletion of RXR-α can make Animals resistant to obesity due to high-fat diets (R).

Colon tumors are associated with the loss of RXR-α expression. Low RAR-β, RAR-γ, and RXR-α expression are also seen in gastric cancer (R, R).

The overexpression of RXR- α and PPAR-α together can increase glucose-stimulated insulin secretion in pancreatic cells. Meanwhile, the suppression of RXR-β in Animals pancreatic cells enhances glucose-stimulated insulin secretion (R).

2) Retinoic Acid Receptors Work Together with PPAR-δ

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and are ligand-activated transcriptional factors. PPAR-δ (PPAR-delta) plays a critical role in inducing lipid metabolism and insulin sensitivity (R).

PPAR-β/δ and RAR jointly control the expression of certain genes. Retinoic acid promotes energy usage by increasing the expression of genes that RAR and PPARβ/δ jointly control (R).

The lack of PPAR can cause problems with metabolism and insulin resistance (R, R).

3) Retinoic Acid Receptors Directly Interact with Thyroid Transcription Factor 1 (TTF-1)

Thyroid transcription factor (TTF-1) and RARs (RARs) directly interact with each other (R).

In human cell culture, there are direct protein-protein interactions between the two transcription factors. The RAR DNA-binding domain and TTF-1 homeodomain mediate their interactions (R).

Both of these transcription factors bind to human surfactant protein B (hSP-B). DNA binding of RAR and TTF-1 to the hSP-B enhancer are critical for protein complex formation and lung development (R).

RAR and TTF-1 interact with each other and depend on the other to help activate gene expression for lung development (R).

Low or no TTF-1 gene expression is associated with a worse prognosis in lung cancer patients compared to patients with a normal gene expression (R).

4) Retinoic Acid Receptor-β Works with Nur77 to Increase Androgen Biosynthesis

Normal human adrenal and gonadal tissues express RAR-β. When RAR-β is activated, it stimulates StAR, CYP17A1, and HSD3B2, which are gene promoters that are involved in androgen (male hormone) production (R).

RAR-β works with Nur77 (another transcription factor) and the gene promoters to increase male hormone production.  Research indicates that Nur77 expression is reliant on RAR-β expression (R).

Without RAR-β or Nur77 expression, the cells do not have enough HSD3B2 promoter activity. This results in a decrease of androgen synthesis (R).

5) Retinoic Acid Receptor-α Works with the Estrogen Receptor-α

The estrogen receptor-α (ER-α) and RAR-α work together to help with estrogen-mediated transcription and cell proliferation in breast cancer cells (R).

RAR-α is also a rate-limiting factor in estrogen synthesis and induces ER-α transcriptional activity. Without this transcription factor, there will be little cell growth (R).

These two transcription factors form part of the same complex in the genome.  While the mechanisms behind this relationship are unknown, researchers have concluded that these two nuclear receptors interact to increase gene transcription in breast cancer cells (R).

6) Retinoic Acid and Vitamin D Help Control the Cell Cycle

Both retinoic acid and vitamin D work to control the cell cycle. RARs and the vitamin D receptor (VDR) can form a protein complex (heterodimerize) with retinoid X receptors (RXRs) (R).

These transcription factors can induce the transcription of common target genes that are involved in the cell cycle. One common gene includes p19INK4D, a cyclin-dependent kinase inhibitor. Induction of p19INK4D protects against UV damage and stops programmed cell death due to DNA damage (R).

Since the vitamin D receptor and RARs can both bind to RXRs, vitamin D can inhibit retinoic acid in GH4C1 (rat) cells. Overexpression of VDR further enhances its repressive effect on retinoic acid and RAR-β2 expression (R).

Lower VDR expression in breast and lung cancer patients is correlated with a lower overall survival rate (R, R).

Other Transcription Factors that May Interact with Retinoic Acid and Its Receptors

  • Transcriptional Intermediary Factor 2 (R)
  • AP-1 (R)
  • TFIIH (R)
  • TAFII135 (R)
  • HNF4-α (R)
  • COUP-TFII (R)

Defects of RAR/RXR Axis Gene Expression

In studies of animals with RAR/RXR defects, common disorders include:

1) Organ Defects

  • Arteries in the wrong position (R)
  • Heart muscle underdevelopment (R)
  • Lung tissue underdevelopment (R)
  • Lung malformation (R)
  • Imperfect development of the kidneys (R)
  • Failure of uterus and vagina development (R)

2) Muscle and Bone Abnormalities

  • Finger tissue defects (R)
  • Defects in the limbs (R)
  • Neckbone abnormalities (R)
  • Vertebrae malformation (R)

3) Eye Malformations

  • Eyelid defects and imperfect development (R)
  • Retina defects (R)
  • Eye membrane defects (R)

4) Glandular Abnormalities

  • Thymus abnormalities (R)
  • Missing thymus lobe (R)
  • Parathyroid gland abnormalities (R)

Additionally, animal studies show that mice without the RAR-α1 and RAR-β genes shortly die after birth from lack of oxygen (R).

Other Technical Details about RAR function

  • In animals, many different parts of the body express the RAR gene. These parts include the brain, spinal cord, eye, inner ear, nose, pituitary gland, thyroid gland, lung, heart, stomach, intestines, liver, pancreas, kidney, gonad, skin, skeletal system, and limbs. These locations indicate RAR’s importance in growth and development (R).
  • RAR-γ removal lowers chondrocyte and proteoglycan expression, which are important factors for joint formation (R).
  • In cells, retinoic acid also decreases IL-12, TNF-α, nitric oxide (NO), PGE2, and COX-2 production (R).
  • RAR coactivators include SRC-1 (NCoA-1), SRC-2 (TIF-2, GRIP-1, and NCoA-2), and SRC-3 (pCIP, ACTR, AlB1, TRAM1, and RAC3) (R).
  • Additionally, RAR-α activation in animals can help protect against HIV-induced kidney damage (R)
  • Rat hearts had a decreased Bcl2/Bax ratio, indicating increased apoptotic cell death in the diabetic heart. ATRA significantly improved the Bcl12/Bax ratio (R).
  • Retinoic acid controls the expression of genes involved in early-onset AD, including MAPT, AβPP, PS, BACE, ADAM10, and APOE (R).

 

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2 COMMENTS

  • Lori Graff

    Very interesting article. However it does not tell us how to Naturally Activate Retinoic Acid Receptors. It is very unclear on how to know if our clients are indeed increasing their Retinoic Acid receptors. Can you give more information on this?

    1. Nattha Wannissorn, PhD

      Good question. Eat food sources of retinol such as liver, eggs, animal fats etc in moderation. Fermented cod liver oil is a good source.

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