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RARs (Retinoic Acid Receptors)

RARs (Retinoic Acid Receptors) are nuclear receptors that regulate gene expression involved in cell growth. They play a critical role in development, reproduction, immunity and organ development.

Contents

Introduction to RARs (Retinoic Acid Receptors)

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

Retinoic Acid Receptors (RARs) are nuclear receptors that are important for proper development of the human body (R).

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 the expression of certain genes. This helps control the organism’s development (R).

RARs consist of 3 subtypes: RAR-α, RAR-β, and RAR-γ. Separate genes encode for each subtype (R).

Vitamin A and its by-product, retinoic acid, control RAR (R).

RARs combine with a protein called RXR (retinoid X receptors) to increase gene expression (R).

By changing gene expression, RARs can inhibit the growth of a large number of tumor cells (R, R).

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

These receptors can be helpful interventions for disorders such as type 2 diabetes, high cholesterol, immune disorders, and various cancers (RRR).

Retinoic Acid Receptors Interact with Other Transcription Factors

1) Retinoic Acid Receptors and Retinoid X Receptors

Retinoic acid receptors (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 let mice become resistant to high fat diet-induced obesity (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 PPARα together can increase glucose-stimulated insulin secretion in pancreatic cells. Meanwhile, the suppression of RXR-β in mice pancreatic cells enhances glucose-stimulated insulin secretion (R).

2) Retinoic Acid Receptors Work Together with PPARβ/δ

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

PPARβ/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 retinoic acid receptors (RARs) directly interact with each other (R).

In human cell culture, there are direct protein-protein interactions between the two transcription factors. The retinoic acid receptor 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) RAR-β Works with Nur77 to Increase Human 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 production (R).

RAR-β works with Nur77 (another transcription factor) and the gene promoters to increase androgen hormone production. Scientists discovered 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) RAR- 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).

Estrogen induces RAR-α expression. Estrogen-mediated cell growth requires RAR-α. It is also a rate-limiting factor 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. However, their mechanisms are unknown. Scientists can only conclude that these two nuclear receptors interact to increase gene transcription in breast cancer cells (R).

6) Retinoic Acid and Vitamin D Work to Control the Cell Cycle

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

Since the vitamin D receptor and retinoic acid receptors 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)

Roles of Retinoic Acid Receptors

1) Retinoic Acid Receptors are Critical For Growth and Development

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Retinoic acid receptors (RARs) are important for development. RAR deficiency can cause many problems to occur during growth.

Mutant 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 are expressed in mice 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. RAR-β absence causes impaired vision in mice (R).

Additionally, embryonic inner ear development in mice needs RAR-α and RAR-γ. Mice without RAR-α expression exhibit hearing deficiency related to middle ear function, indicating its importance for hearing (R).

Mice 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 mice, decreased expression of RAR-γ leads to birth defects and growth deficiency. It 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 mice embryos (R).

RAR-γ plays a critical role in hematopoiesis, the process in which the body creates new blood cells. In mice, retinoic acid receptors help maintain the balance between the regeneration of blood originating cells and their production (R).

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

Retinoic acid receptors are also needed in the growth and development of important organs, such as the heart, lungs, and digestive tracts. Without RAR-α, β, or γ gene expression, tissue formation in these organs will be dysfunctional (R).

2) Retinoic Acid Receptors Increase Metabolism

Retinoic acid is important for energy metabolism. It helps activate the gene expression of cells involved in metabolism (R).

Retinoic acid receptors (RARs) bind to retinoic acid response elements in the target gene and then increase the genes’ expressions, thus increasing energy usage (R).

Activated RAR promotes energy usage, especially in fat cells (R).

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

3) Retinoic Acid Receptors Improve Insulin Sensitivity

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Retinoic acid and retinoic acid receptor (RAR) activity also improved insulin sensitivity and glucose tolerance in obese mice (R).

In adult mice, pancreatic β cells need RAR activity. Without RAR activity, the mice had a lower blood insulin level and impaired glucose-stimulated insulin secretion (R, R).

Inhibition of RAR activity in adult mice decreases β-cell insulin secretion. Without RARs, the balance of glucose is disturbed (R).

4) Retinoic Acid Receptors Activate the Immune Response

Retinoic acid and its receptors (RARs) play important roles in the immune system. They play a part in immune cells production and the immune response. Without retinoic acid, defects in the immune system can cause many problems (R).

Retinoic acid and RAR activity occurs in B cells, T cells, and other lymphocytes (white blood cells) (R).

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

RAR activation and retinoic acid activity control the development of various immune cells. They initiate the production of T-cells, FoxP3 T regulatory cells, CD4+, and CD8+ cells (R).

Additionally, retinoic acid and RAR activity suppresses pro-inflammatory activity (R).

5) RAR-α Activation Helps Keep Cholesterol Levels Balanced

The ABC transporter G1 (ABCG1) gene plays a role in maintaining the balance of the body’s cholesterol levels. The flowing out of cholesterol (efflux) helps prevent high cholesterol and keeps cholesterol levels balanced (R, R).

In human cell culture, all-trans-retinoic acid activated retinoic acid receptors (RARs). RAR-α then increased ABCG1 transcription, which led to an increase in cholesterol ejection from macrophages (a type of white blood cell) (R).

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

Alzheimer’s disease is characterized by memory loss and brain/nerve inflammation.

Retinoic acid receptors (RARs) are needed for learning and memory (R).

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

One chromosome, 12q13, is associated with late-onset Alzheimer’s disease. The gene that encodes RAR-γ is located at 12q13. Additionally, retinoic acid is able to control the expression of genes involved in early-onset Alzheimer’s disease (R).

Since retinoic acid and its receptors are involved in a variety of pathways that affect Alzheimer’s disease, it can potentially be used in therapy for the disorder (R).

7) RAR Activity Protects Heart Cells from Diabetes-Induced Death

Diabetes can be a risk factor for heart disease. High blood sugar can induce programmed cell death (apoptosis) in heart cells. In addition to having anti-diabetic effects, retinoic acid receptors (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 RAR and RXR, as well as RAR-α/RXR-α activity, inhibited cell death. RAR-α and RXR-α are required for maintaining heart cell survival (R).

8) Retinoic Acid Receptors Positively Influences Sleep Quality

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RAR-β expression influences delta wave activity during slow wave sleep. Delta wave activity stimulates the release of several growth hormones and helps with development. Vitamin A deficiency and the lack of RAR-β expression reduces delta power (R, R).

There is a link between memory, learning, and sleep. Aging can negatively affect memory consolidation during sleep(R).

In mice, the administration of Am80, a retinoic acid receptor (RAR) activator, improved REM sleep. RAR activation can reduce the deteriorating effects of age on sleep quality (R).

9) Retinoic Acid Receptor Function is Essential for Male Fertility

Sperm formation needs all-trans retinoic acid (ATRA). ATRA is able to help with sperm formation by activating retinoic acid receptors (R).

RAR-α deficiency in male mice leads to sterility. Disruption of the RAR-α gene can lead to testis degeneration and an inhibition of sperm creation (RR).

10) Retinoic Acid Receptors May Contribute to Skin Aging

Retinoic acid receptors RAR-α and RAR-γ have high expression in skin cells. Skin development requires these receptors (R).

However, RAR-α expression may play a role in skin aging. In human skin cells, a significant increase of RAR-α mRNA and protein 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).

Retinoic Acid Receptors and Immune Diseases

1) Retinoic Acid Receptors Mostly Suppress Tumors 

Lung Cancer

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

The loss of RAR-β expression 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 mice. 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 has lung tumor–suppressor activity (R).

Two hypotheses might be able to explain these conflicting results. During lung cancer, RAR-β is inactive and cannot suppress tumors. Or, 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 gastric (stomach) cancer tissue 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 be a new treatment strategy for stomach cancer (R).

Oral Cancer

RAR-β expression in oral cancer cells is associated with a higher 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).

On the other hand, 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).

2) Retinoic Acid Receptors Can Help Prevent Leaky Gut

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Leaky gut, or intestinal permeability, is a condition where the outer tissue layer of the intestines (epithelium) has an increased permeability. This means that microbes, toxins, and food particles can “leak” into the blood and other parts of the body. Leaky gut is associated with several autoimmune diseases (R).

Vitamin A and retinoids are essential nutrients for tissue production and differentiation (the process where a cell becomes more specialized). Retinoic acid acts via the retinoic acid receptors (RARs) and retinoid X receptors (RXRs) to help differentiate gut tissue. Vitamin A supplementation in healthy children improved gut function, while Vitamin A deficiency reduced intestinal function (R).

Retinoic acid treatment in human cell culture assisted with intestinal differentiation (production), which increased the integrity of the outer intestinal layer. This helps prevent leaky gut (R).

Intercellular tight junctions help keep the intestinal epithelial barrier in place. All-trans retinoic acid helps form tight junctions through a specific retinoic acid receptor/retinoid X receptor compound (R).

When scientists treated MDCK (canine cell) culture with RAR-α stimulants, it enhanced the expression of tight junction-associated genes. RAR-α helped maintain barrier function and helped reduce the breakdown of the intestinal barrier (R).

Additionally, retinoic acid depletion leads to the disruption of functional tight junctions and increases gut permeability (R).

3) Retinoic Acid Receptors Can Potentially Treat Multiple Sclerosis

In mice, all-trans retinoic acid (ATRA, an activator of retinoic acid receptors) was able to reduce the severity of experimental autoimmune encephalomyelitis. This condition is the animal model of multiple sclerosis, and studies of this disorder may provide more information about human diseases (R).

In mice, ATRA and Am80, a synthetic RAR-α and RAR-β activator, suppressed inflammation in optic nerve fibers. The activation of the retinoic acid receptors helped reduce the severity of the disease and protected the optic nerve. This suggests that retinoic acid may potentially help treat multiple sclerosis in humans (R).

4) RAR-α Might Induce Inflammation

Inflammatory cells express retinoic acid receptors (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).

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 retinoic acid receptors (RARs) (R).

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

The main sources of carotenoids are plants. Primary dietary sources are fruits and vegetables, such as tomatoes, spinach, carrots, sweet potatoes, and peppers. Bread, eggs, milk, cheese, meat, poultry, and oils also contain carotenoids (R).

However, not all carotenoids can increase RAR activity. β-carotene does not significantly activate RARs when compared to all-trans retinoic acid (R).

Defects of RAR/RXR Axis Gene Expression

In mutant mice with RAR/RXR defects, common disorders include:

1) Organ Defects

  • Arteries are 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, mice without the RAR-α1 and RAR-β genes shortly die after birth from the lack of oxygen (R).

Technical

  • In mice, many different parts of the body express the RAR gene. They include the brain, spinal cord, eye, inner ear, nose, pituitary and thyroid glands, 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 COX2 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 mice 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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