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RARs (Retinoic Acid Receptors)

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

Introduction to RARs (Retinoic Acid Receptors)

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Retinoic Acid Receptors (RARs) are transcriptional proteins important for proper development of the human body. They consist of 3 subtypes α, β,γ  encoded by separate genes (R).

RXR‘s are found in all parts of the skin (R).

Vitamin A and its byproduct (retinoic acid) control RAR.

They combine with the protein called RXR (retinoid X receptors) to increase gene expression. By changing gene expression (R) (R), RARs inhibit the growth of a large number of  tumor cells (R).

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

They can be helpful interventions for disorders such as diabetes type 2, high cholesterol, atherosclerosis, skin disorders and cancer (R1, R2, R).

RARs may prevent lung, liver and breast cancer (R) (R).

Health Benefits of Retinoic Acid Receptors

1) Retinoic Acid Receptors are Critical For Growth and Development

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RARs (Retinoic Acid Receptors) combine without proteins to increase gene expression (RXR) (R1, R2).

Absolute deficiency of RAR-α in male mice leads to sterility due to inhibition of sperm creation (R, R1).

RAR-γ helps produces factors important for joints (chondrocytes, proteoglycans) (R).

Decreased expression of RARγ leads to birth defects, growth deficiency, bone and vessel defects, premature death and male sterility.

RAR-β absence causes impaired vision and movement.

Suppression of RARs due to vitamin A deficiency contributes to embryonic skeleton underdevelopment (R). In adults, it leads to impaired vision and skin disorders.

2) Retinoic Acid Receptors Increase Metabolism

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Retinoic acid suppresses obesity by promoting energy expenditure and decreases fat tissue (R).

RA increases energy expenditure and insulin sensitivity (R).

3) Retinoic Acid Receptors Represses Insulin Resistance

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RAR (with RXRs) shows antidiabetic effects via increasing insulin release and insulin sensitivity (R)(R).

Retinoic acid  increases  expression of the insulin-signaling gene PDK1 thus increasing fat breakdown and reducing triglyceride content (R).

4) Retinoic Acid Receptors Help Rheumatoid Arthritis

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Trans-retinoic acid shows anti-inflammatory effects in rheumatoid arthritis via decreasing TNF (R).

Retinoic acid also increases Tregs and inhibits Th17.

5) Retinoic Acid Receptors Help Osteoporosis

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RARs (Retinoic Acid Receptors) inhibit bone degrading cells, which may be beneficial in the treatment of osteoporosis (R).

6) Retinoic Acid Receptors and Cancer 

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In the vast majorities of studies, increased expression of RAR-α was associated with cellular proliferation leading to cancer (R).

RAR-α helps prevent acute promyelocytic leukemia M3 (R).

RARβ2 has tumor suppressor activity (R, R).

Lung Cancer

RAR-γ is essential for the normal alveoli development in the lung.

RARs and RXRs possess inhibitory effects on non-small cell lung cancer (NSCLC) cell growth.

Increased RAR-β expression is a prognostic factor of poor outcome in stage I NSCLC (R).

RAR and RXR in tumor tissue is a promising prognostic biomarker for chemopreventive trials in NSCLC (R).

Breast cancer

RXR-β reduces migration of human breast cancer cells and its loss is an early event during mammary carcinogenesis (R).

Decreased levels of RARβ5 characterize the conversion of non-invasive breast cancer into an invasive disease (R). It is a potential target for  retinoid therapy in breast cancer (R).

Stomach Cancer

Retinoic acid receptors are expressed in epithelial gastric cancer. Decreased expression of RAR–α  may be an indicator of a positive prognosis.

RARs are potent chemotherapeutic drugs regarding their ability to prevent cell differentiation, proliferation and malignant transformation in gastric cancer cells (R).

Ovarian Cancer

RAR-α and RXR-β are highly expressed in advanced stages of ovarian cancers.

Abnormal expression of the RAR-β gene enhances the tumorigenicity of human papillomavirus type 18-transformed ovarian cancer cell (R).

Therefore, elevated levels of RAR-α are negative predictors of survival in an advanced ovarian tumor (R).

7) Retinoic Acid Receptors Control Hematopoietic Development

RARα  induces granulocytic differentiation, RARγ plays a critical role in maintaining the balance between the regeneration of blood originating cells and their differentiation (R).

8) Retinoic Acid Receptors Regulate Immune Response

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They are in charge of  immune cells differentiation, immune response and host protection against various infections and autoimmune disorders.

RARs are control effectors of the development of various immune cells (T-cells, FoxP3 T regulatory cells, gut associated T regulatory cell differentiation, CD4+, CD8+ cell).

RA suppresses Th17 cell differentiation via promoting TGF-β and inhibits the stimulators of Th17 growth – IL-6R, IFN regulatory factor 4, IL-23R (R).

RA is of highly importance in the gastrointestinal local immunity, mostly concentrated in the mesenteric lymph nodes, Payer’s patches and lamina propria.

RA induces the migration of leukocytes to the mucosa of the intestines which  multiplies its immunity (R).

Toxoplasmosa gondi infected patients have lost  Th1 and Th17 response, due to impaired retinoic acid signaling, leading to innability to suppress the infection (R).

9) Retinoic Acid Receptors act against infective diseases

RA is essential for host resistance to infections and transplantation graft rejections (R).

RARs  are able to fight against pathogens in chronic helminth infection as well as acute small intestine inflammation (R).  

10) Defects of Retinoic Acid Receptors may initiate the Parkinson disease

RARβ and  RARγ are highly expressed in the brain regions that have dopaminergic neurons. Dopamine receptor 2 absence in the mouse imitates the human Parkinson’s disorder.

RAR/RXR dimers specifically increase the levels of this receptors, thus may promote the onset of this disease (R).

Defects of RAR/RXR Axis Gene Expression

The most common disorders due to the RAR/RXR defects are as follows:

1) Cardio-vascular system defects in RXRα/RAR mutants

  • abnormalities of the great arteries near the heart and its septum
  • heart muscle underdevelopment (R).
  • deviant cephalic arteries (R).

2) Locomotor Abnormalities

  • interdigital mesenchyme regression
  • soft tissue finger defects
  • limb bones defects
  • craniofacial abnormalities of the bones

3) Urogenital Abnormalities

  • kidney and ureter defect in RXRα/RAR mutants
  • Müllerian duct imperfect development (R).

4) Ocular Malformations

  • eyelid defects and front segment imperfect development
  • defects of retina
  • eye membrane defects (R).
  • RA-dependent eye differentiation is orchestrated by the NCC-derived periocular mesenchyme (R).

5) Glandular Abnormalities 

  • thymus and parathyroid gland abnormalities (R).

How to naturally increase the level of RARs ?

Carotenoids (b-carotene, a-carotene,b-cryptoxanthin, lycopene, lutein, and zeaxanthin) are the main source of vitamin A that increase the level of retinoic acid pathway molecules (retinol, retinal, retinoic acid).

Their main sources are plants and photosynthetic microorganisms. Primary dietary sources are fruits and vegetables, as well as bread, eggs, milk, beverages, fats and oils.

RAR Modulators

  • ATRA (tretinoin)
  • 9-cis (alitretinoin)
  • 13-cis (isotretinoin)

EC 23 is an analog of ATRA and stimulates stem cells and neurogenesis.

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