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)
- Health Benefits of Retinoic Acid Receptors
- 1) Retinoic Acid Receptors are Critical For Growth and Development
- 2) Retinoic Acid Receptors Increase Metabolism
- 3) Retinoic Acid Receptors Represses Insulin Resistance
- 4) Retinoic Acid Receptors Help Rheumatoid Arthritis
- 5) Retinoic Acid Receptors Help Osteoporosis
- 6) Retinoic Acid Receptors and Cancer
- 7) Retinoic Acid Receptors Control Hematopoietic Development
- 8) Retinoic Acid Receptors Regulate Immune Response
- 9) Retinoic Acid Receptors act against infective diseases
- 10) Defects of Retinoic Acid Receptors may initiate the Parkinson disease
- Defects of RAR/RXR Axis Gene Expression
- RAR Modulators
Introduction to RARs (Retinoic Acid Receptors)
Vitamin A and its byproduct (retinoic acid) control RAR.
RARs are important for embryonic development, organ generation, vision, immune functions, energy production and fertility (R).
Health Benefits of Retinoic Acid Receptors
1) Retinoic Acid Receptors are Critical For Growth and Development
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.
2) Retinoic Acid Receptors Increase Metabolism
RA increases energy expenditure and insulin sensitivity (R).
3) Retinoic Acid Receptors Represses Insulin Resistance
4) Retinoic Acid Receptors Help Rheumatoid Arthritis
5) Retinoic Acid Receptors Help Osteoporosis
RARs (Retinoic Acid Receptors) inhibit bone degrading cells, which may be beneficial in the treatment of osteoporosis (R).
6) Retinoic Acid Receptors and Cancer
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).
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).
RXR-β reduces migration of human breast cancer cells and its loss is an early event during mammary carcinogenesis (R).
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).
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
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.
- ATRA (tretinoin)
- 9-cis (alitretinoin)
- 13-cis (isotretinoin)
EC 23 is an analog of ATRA and stimulates stem cells and neurogenesis.