Lipid Soluble Vitamins: A, D, E, and K

Lipid Soluble Vitamins

• The lipid-soluble vitamins are A, D, E, and K.
• These vitamins are soluble in lipids but not in aqueous solutions.
• They are important in vision, bone formation, act as antioxidants, and aid in blood clotting.
• The body stores lipid-soluble vitamins.

Vitamin A

• Retinoids, related to dietary retinol, are essential for vision, reproduction, growth, epithelial tissue maintenance, and immune function.
• The RDA for adults is 700 𝜇g (female) and 900 𝜇g (male) retinol activity equivalent (RAE).
• 1 RAE is equivalent to 1 𝜇g of retinol, 12 𝜇g of β-Carotene, or 24 𝜇g of other carotenoids.
• Retinol activity equivalents are the active forms of Vitamin A.
• Vitamin A is a collective term for biologically active molecules.
• Vitamin A exists in two major forms: retinoids and carotenes.
• Retinoids include retinol, retinal, and retinoic acid.
• Carotenes include α-carotene, β-carotene, and γ-carotene.

Structure and Function

• Retinol is found in animal tissue as retinyl ester with long-chain fatty acids.
• Retinal is derived from the oxidation of alcohol.
• Retinoic acid is derived from the oxidation of retinal and cannot be reduced in the body.
• β-Carotene is oxidized in the intestine and yields two molecules of retinal.
• The conversion of β-Carotene is inefficient, and its vitamin activity is about 1/12 that of retinol.

Absorption and Transportation

• Retinyl esters and β-Carotene are hydrolyzed to retinol and FFAs for transport to the liver.
• Retinol is re-esterified in the intestinal mucosa, packed into chylomicrons, and sent to the liver.
• Retinol is released from the liver and transported to extrahepatic tissues by retinol-binding protein (RBP).

Mechanism of Action

• Retinol is oxidized to retinoic acid which binds to a specific retinoic acid receptor (RAR) protein in the nucleus.
• The activated retinoic acid RAR complex binds to chromatin and regulates gene transcription.
• RAR proteins are part of a superfamily of transcriptional regulators.
• Nuclear receptors for steroid and thyroid hormones and 1,25-dihydroxycholecalciferol included in RAR proteins superfamily.

Vitamin A Function

• Rhodopsin consists of 11-cis retinal bound to protein opsin which is a visual pigment of rod cells in the retina.
• When rhodopsin is exposed to light, pigment releases all-trans retinal and opsin after photochemical reactions.
• Regeneration of rhodopsin requires isomerization of all-trans back to all 11-cis retinal.
• Similar reactions are responsible for color vision in the cone cells.
• Vitamin A is essential for normal differentiation of epithelial cells and mucus secretion, and is therefore essential for the body's barrier defense against pathogens.
• Retinol and retinal are essential for normal production, supporting spermatogenesis, and preventing fetal resorption.
• Even though retinoic acid is inactive in maintaining reproduction and the visual cycle, it promotes growth and differentiation of epithelial cells.
• Animals given vitamin A only as retinoic acid from birth are blind and sterile.

Vitamin A Deficiency and Treatment

• Vitamin A deficiency can be treated with administration of retinol or retinyl ester.
• Night blindness is one of the earliest signs of vitamin A deficiency and prolonged deficiency can lead to irreversible loss of visual cells.
• Severe vitamin A deficiency leads to xerophthalmia, a pathologic dryness of the conjunctiva and cornea.
• Untreated xerophthalmia leads to blindness and is most common in children in tropical countries.
• Symptoms of Vitamin A deficiency include dry skin, poor immunity, and slow growth.

Acne and Psoriasis Treatment

• Retinoic acid or its derivative is used to treat acne and psoriasis.
• Mild cases are treated with topical applications while severe cases are treated with orally administered 13-cis retinoic acid.

Toxicity

• Hypervitaminosis A is caused by excessive intake of Vitamin A, above 7.5 mg/day of retinol.
• Symptoms of Vitamin A toxicity include dry and pruritic skin due to increased keratin synthesis, an enlarged liver, and decreased mineral absorption.
• Pregnant women should avoid excess vitamin A due to the risk of malformations in the developing fetus.
• The drug, Isotretinoin, used to treat cystic acne, should not be given to pregnant women or those trying to become pregnant.
• Adequate birth control must be used before initiation of Isotretinoin prescriptions.

Vitamin D

• D vitamins are a group of sterols sharing hormone-like functions.
• The active molecule is 1,25-dihydroxycholecalfiferol [1,25-diOH-D3].
• 1,25-diOH-D3 binds to intracellular receptor proteins and interacts with DNA to stimulate or repress gene transcription, this is similar to Vitamin A
• RDA for individuals aged 1-70 years is 15 𝜇g/day, and 20 𝜇g/day for those >70 years old.
• Breast milk is not a good source of Vitamin D, supplementation is required for babies.

Vitamin D Sources

• 7-Dehydrocholesterol, an intermediate in endogenous cholestrol synthesis, is converted to cholecalciferol in the dermis and epidermis with sunlight exposure. 
• Cholecalciferol is transported to the liver to be converted to calcidiol.
• Ergocalciferol (D2 from plants) and cholecalciferol (D3 from animals) are dietary sources of Vitamin D, and they get packed into chylomicrons.

Vitamin D Metabolism

• Ergocalciferol (D2) and cholecalciferol (D3) are not biologically active until converted in vivo.
• The first hydroxylation occurs at the 25 position to form 25-hydroxycholecalciferol [25-OH-D3] in the liver.
• A further hydroxylation happens at the 1 position, in the kidney, forming 1,25-dihydroxycholecalfiferol [1,25-diOH-D3].
• Phosphate and calcium regulate the synthesis of [1,25-diOH-D3].

Vitamin D Function

• 1,25-diOH-D3 functions to maintain adequate plasma levels of calcium by increasing uptake of calcium in the intestine.
• Another function is to minimize calcium loss by increasing reabsorption in the kidney.
• This vitamin stimulates resorption of bone when blood calcium is low.
• 1,25-diOH-D3 enters the intestinal cell and binds to cytosolic receptor, enhances synthesis of calbindin (specific Ca-binding protein), increasing calcium uptake.
• 1,25-diOH-D3 stimulates mobilization of calcium from bone via necessary process requiring protein synthesis and the presence of PTH, which leads to increase in both plasma calcium and phosphate.

Calcitonin

• Calcitonin, a thyroid hormone, decreases blood calcium by inhibiting mobilization from bone, absorption from the intestine, and reabsorption by the kidney and it opposes the actions of PTH.

Clinical Indications of Vitamin D

• Vitamin D deficiency causes a net demineralization of bone resulting in rickets (in children) and osteomalacia (in adults).
• Rickets is when Collagen is continually formed but incomplete mineralization results in it being soft.
• Osteomalacia is when demineralization of preexisting bones increases their susceptibility to fracture.
• Renal Osteodystrophy is when chronic kidney disease decreases the ability to process vitamin D while also retaining phosphate.
• This results in hyperphosphatemia and hypocalcemia as well as low blood calcium levels, increasing PTH levels, which releases calcium and P to bones → bone demineralization.
• Calcitriol and phosphate reduction therapy will prevent further bone loss.
• Hypoparathyroidism is lack of PTH which results in hypocalcemia and hyperphosphatemia.
• Hypoparathyroidism can be treated with calcitriol (1,25-diOH-D3) and calcium supplements can treat said symptoms.

Toxicity of Vitamin D

• Toxicity occurs when intake is high (100,000 IU) for weeks or months
• Symptoms include loss of appetite, nausea, thirst, and stupor.
• Toxicity is only seen with supplemental use not naturally.
• Excess Vitamin D produced in the skin is converted to inactive forms.

Vitamin K

• Vitamin K’s principal role is in the post-translational modification of proteins involved in blood clotting.
• Vitamin K acts as a coenzyme in the carboxylation of certain glutamic acid residues.
• Vitamin K exists in many forms; in plants as phylloquinone (K1), and intestinal bacteria as menaquinone (K2).
• A synthetic form of Vitamin K is menadione, able to be converted to K2.
• The RDA for Vitamin K is 90 𝜇g/day (female) and 120 𝜇g/day (males).

Vitamin K Functions

• Vitamin K is required in the hepatic synthesis of blood clotting proteins, including factors II, VII, IX, and X.
• Vitamin K gets oxidized during carboxylation of glutamate residue, whereas it can be inhibited via Warfarin a analog that’s given to avoid thrombosis.
• Gla residues are good Ca chelators because of their two negatively charged carboxylate groups.
• A prothrombin-Ca complex is able to bind to negatively charged membrane phospholipids on the surface of damaged endothelium and platelets, leading to an increase thrombin production from prothrombin.

Vitamin K Deficiency

• Vitamin K deficiency is rare since it’s synthesized by intestinal bacteria and also found in diet.
• A decrease in the bacterial population can result in the creation of hypoprothrombinemia.
• Vitamin K is found in many supplements to correct any issues.
• An exception: newborns have sterile intestines, so they’re unable to synthesize vitamin K. Therefore, they are given a single shot of Vitamin K.

Vitamin K Toxicity

• Prolonged administration of large doses of synthetic vitamin K may result in hemolytic anemia and jaundice in infants due to toxic effects on the membrane of RBCs.

Vitamin E

• Vitamin E consists of eight naturally occurring tocopherols, with α-tocopherol being the most active.
• Vitamin E's primary function is an antioxidant to prevent nonenzymatic oxidation, such as peroxidation of polyunsaturated FAs.
• The RDA is 15 mg per day and the requirement increase when intake of PUFA increases.

Vitamin E Deficiency

• Newborns have low reserves of vitamin E, breast milk and formulas provide it.
• Very-low-birth-weight may be given supplements.
• Usually linked to defective lipid absorption or transport.

Clinical Uses and Toxicity

• It is not recommended for the prevention of chronic diseases, coronary heart diseases or cancer as some show increased signs of strokes.
• In fat-soluble vitamins, it’s the least toxic.
• No toxicity has been found at doses of 300mg/day (UL=1,000mg/day)

Multiple Choice Questions

• The vitamin-endocrine gland pair that work together is Vitamin D-Thyroid.
• Vitamin A is a vitamin treatment associated with acne treatment.
• The conversion of carotenoids to Vitamin A takes place in the Intestine,.
• Vitamin A is useful in cancer.
• Vitamin K acts as a carboxylase for the formation of γ-carboxy glutamate
• Cholesterol is a precursor in the biogenesis of Vitamin D.