Answer- Retinoic acid (RA) and its isomers act as hormones to affect gene expression and thereby influence numerous physiological processes.
All- trans retinoic acid and 9-cis retinoic acid have active role in growth, development and tissue differentiation. They have different actions in different tissues.
Mechanism of regulation of gene expression
Like vitamin D, retinoic acid interacts with nuclear receptors that bind to control elements which are specific regions on the DNA to regulate the expression of specific genes.
There are two families of nuclear retinoid receptors (RAR) that bind to All- trans retinoic acid or 9-cis retinoic acid and RXR that bind to 9-cis retinoic acid and to some of the other physiologically active retinoids. RXR can form active dimer with RAR and the receptors for calcitriol, thyroid hormone and the receptors for long chain fatty acid derivatives. The result is that a large number of genes are sensitive to control by retinoic acid.
All-trans-RA and 9-cis-RA are transported to the nucleus of the cell bound to cytoplasmic retinoic acid-binding proteins. Within the nucleus, all-trans-RA binds to retinoic acid receptors (RAR) and 9-cis-RA binds to retinoid receptors (RXR). RAR and RXR form RAR/RXR heterodimer, which bind to regulatory regions of the chromosome called retinoic acid response elements (RARE). Binding of all-trans-RA and 9-cis-RA to RAR and RXR respectively allows the complex to regulate the rate of gene transcription. Nuclear Receptors in the Gonads increase gene expression and maintain reproductive tissues while nuclear receptors in epithelial cells regulate cell differentiation. Through the stimulation and inhibition of transcription of specific genes, retinoic acid plays a major role in cellular differentiation, the specialization of cells for highly specific physiological roles. Many of the physiological effects attributed to vitamin A appear to result from its role in cellular differentiation(Figure-1)
Figure-1- showing the role of retinoic acid in gene expression.
Q.2- What is visual cycle? What is the role of vitamin A in visual cycle?
Answer- In the retina, retinaldehyde functions as the prosthetic group of the light-sensitive opsin proteins, forming rhodopsin (in rods) and iodopsin (in cones). Any one cone cell contains only one type of opsin, and is sensitive to only one color. In the pigment epithelium of the retina, all-trans-retinol is isomerized to 11-cis-retinol and oxidized to 11-cis-retinaldehyde. This reacts with a lysine residue in opsin, forming the holoprotein rhodopsin.
As shown in Figure-2, the absorption of light by rhodopsin causes isomerization of the retinaldehyde from 11-cis to all-trans, and a conformational change in opsin. This results in the release of retinaldehyde from the protein, and the initiation of a nerve impulse. The formation of the initial excited form of rhodopsin, bathorhodopsin, occurs within picoseconds of illumination. There is then a series of conformational changes leading to the formation of metarhodopsin II, which initiates a guanine nucleotide amplification cascade and then a nerve impulse. The nerve impulse generated by the optic nerve is conveyed to the brain where it can be interpreted as vision. The final step is hydrolysis to release all-trans-retinaldehyde and opsin. The key to initiation of the visual cycle is the availability of 11-cis-retinaldehyde, and hence vitamin A. By a series of reactions all trans retinol is converted to 11-cis- retinal which reassociates with opsin to form Rhodopsin. In deficiency, both the time taken to adapt to darkness and the ability to see in poor light are impaired.
Figure-2- showing the role of vitamin A in visual cycle
Vitamin A deficiency and vision
Vitamin A deficiency (VAD) among children in developing nations is the leading preventable cause of blindness. The earliest evidence of vitamin A deficiency is impaired adaptation to darkness (nyctalopia), which can lead to night blindness.
- Bitot spots – Areas of abnormal squamous cell proliferation and keratinization of the conjunctiva can be seen in young children with VAD.
- Xerophthalmia results from keratinization of the conjunctiva.
- Keratomalacia- In advanced deficiency; the cornea becomes hazy and can develop erosions, which can lead to its destruction (Keratomalacia).
- Blindness due to retinal injury – Vitamin A has a major role in photo transduction.. VAD leads to a lack of visual pigments; this reduces the absorption of various wavelengths of light, resulting in blindness.
Q.3- Why is vitamin A commonly called Anti-infective vitamin?
Why do the children deficient in vitamin A get more prone to respiratory and gastrointestinal infections?
Answer- Vitamin A is commonly known as the anti-infective vitamin, because it is required for normal functioning of the immune system, and even mild deficiency leads to increased susceptibility to infectious diseases.
1) Vitamin A and retinoic acid (RA) play a central role in the development and differentiation of white blood cells, such as lymphocytes, which play critical role in the immune response. Activation of T-lymphocytes, the major regulatory cells of the immune system, appears to require all-trans-RA binding of RAR.
2) The skin and mucosal cells (cells that line the airways, digestive tract, and urinary tract) function as a barrier and form the body’s first line of defense against infections. Retinol and its metabolites are required to maintain the integrity and functioning of these cells. Keratinizations of mucous membranes in vitamin A deficiency add up to the risk to infections.
3) The onset of infection reduces blood retinol levels very rapidly. This phenomenon is generally believed to be related to decreased synthesis of retinol binding protein (RBP) by the liver, since it is a negative ‘Acute phase protein’, that results in decreased circulatory concentration of the vitamin with further deterioration of the immune system. In this manner, infection stimulates a vicious cycle.
4) Vitamin A also plays a role in iron utilization, humoral immunity, T cell–mediated immunity, natural killer cell activity, and phagocytosis.
All the components of immune system are affected in deficiency. Hence in brief it can be said that the pathogenic invasion is enhanced and immune system is weakened in vitamin A deficiency leading to increased susceptibility to infections.
Q.4- How does Zinc deficiency affect the functioning of vitamin A?
Answer- Zinc deficiency is thought to interfere with vitamin A metabolism in several ways: (1) zinc deficiency results in decreased synthesis of retinol binding protein (RBP), which transports retinol through the circulation to tissues (e.g., the retina) and also protects the organism against potential toxicity of retinol; (2) zinc deficiency results in decreased activity of the enzyme that releases retinol from its storage form, retinyl palmitate, in the liver; and (3) zinc is required for the enzyme that converts retinol into retinal. Thus zinc deficiency precipitates vitamin A deficiency producing a variety of symptoms.
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