Lipid-soluble Vitamins PDF

Lipid-soluble Vitamins Marks’ Basic Medical Biochemistry , 6th Ed pages: 13-16 Biochemistry, Cell and Molecular Biology, and Genetics Part VI Chapter 46 (386-391) Zeynep Gromley, Ph.D. MANS 429 [email protected]...

Lipid-soluble Vitamins Marks’ Basic Medical Biochemistry , 6th Ed pages: 13-16 Biochemistry, Cell and Molecular Biology, and Genetics Part VI Chapter 46 (386-391) Zeynep Gromley, Ph.D. MANS 429 [email protected] 1  Learning Objectives Explain the cellular and physiological functions of vitamin D Describe the synthesis of vitamin D Explain the mechanisms of vitamin D actions Discuss the effects of vitamin D on calcium homeostasis Explain the consequences of vitamin D deficiency Describe clinical symptoms due to excess or deficiency of vitamin A Describe clinical symptoms due to deficiency of vitamin K Explain the molecular action of vitamin K antagonists (e.g., warfarin) Explain the cellular and physiological functions of vitamin E Distinguish differences of disorders associated with vitamin A, D, E, K 2 ADEK 3  Cholesterol is precursor for vitamin D 7-dehydrocholesterol forms in the liver and is transported to the skin. 7-dehydrocholesterol is converted to vit-D3 (cholecalciferol) when skin is exposed to UV light. Vit-D3 is transported to the liver. Cholecalciferol is hydroxylated in the liver to form 25- hydroxycholecalciferol (25-OHD3) 1-α-hydroxylase in the kidney hydroxylates the carbon-1 to form calcitriol (1,25-dihydroxycholecalciferol 1,25(OH)2-D3 Calcitriol is the biologically active form of vitamin D 4  Regulation of Vitamin D Synthesis Hypocalcemia stimulates secretion of parathyroid hormone (PTH). PTH activates 1 α-hydroxylase in the kidney 1α-hydroxylase is also activated by hypophosphatemia Increased production of calcitriol downregulates its own synthesis through negative feedback mechanism. 5  Functions of Vitamin D Calcium and phosphorus homeostasis: maintenance of adequate levels of plasma calcium and phosphorus Bone mineralization Non-skeletal health benefits of Vit-D Recent studies found that Vit-D possibly prevents development of: ― Cancer (antiproliferative effects) ― Cardiovascular diseases ― Diabetes ― Autoimmune disorders (immunomodulatory effects) ― Cognitive decline 6 Functions of Vitamin D GI tract: induces synthesis of Ca2+binding proteins (calbindin), increases absorption of calcium and phosphate from intestine Calbindin stimulates ATP-dependent calcium pump, which transports calcium into blood. Kidneys: stimulates reabsorption of calcium Bone: activates osteoblasts to synthesize the calcium- binding protein osteocalcin and increases bone mineralization. Net effect: Calcitriol maintains calcium at supersaturated levels in the plasma for maintenance of bone mineralization or density 7  Mechanisms of Steroid Hormones Actions Steroid/Thyroid hormones are lipophilic and can pass through the plasma membrane unaided Bind to intracellular receptors (in cytoplasm or nucleus) 8  Intracellular Receptors 1. Steroid Hormone Receptor Family Glucocorticoid Receptor (GR) Mineralocorticoid Receptor (MR) Androgens Receptor (AR) Progesterone Receptor (PR) 2. Thyroid Hormone Receptor Family Thyroid hormone Receptor (TR) Retinoic Acid Receptor (RAR) Retinoid X Receptor (RXR) Estrogen Receptor (ER) Peroxisome Proliferator-Activated Receptor (PPAR) Vitamin D Receptor (VDR) 9  Vit-D (calcitriol) binds to the Vit-D receptor (VDR), which associates with RXR forming heterodimeric complex. This heterodimeric complex binds to Vit-D response elements (VDRE) located on the promoter region of the Vit-D target genes. Activated genes creates new mRNA and translation of mRNA produces proteins for cellular processes. Genes that are involved in Calcium homeostasis Bone mineralization 10 Deficiency of Vitamin D Normal plasma levels of 25-(OH)-D is 20 – 100 ng/mL. Deficiency can be due to limited exposure to sun (most common) Diet, malabsorption disorders Renal disorders Rare genetic disorders (deficiency of 1α-hydroxylase) Medication side effects (steroids, phenytoin, rifampin) Vitamin D deficiency impairs mineralization of bones 11 Vitamin D deficiency reduces the intestinal calcium absorption and can cause Rickets (in children) and osteomalacia (in adults) Rickets: due to insufficient calcium, osteoblasts are unable to form hydroxyapatite ( Ca10(PO4)6(OH)2 ) Softened bones bend easily. Effects the spine, pelvis, and tibia. Osteomalacia: Reduced plasma calcium causes release of PTH, which mobilizes calcium from bones, which gradually drained of their mineral content. Bones exhibit normal amount of collagen matrix but deficient mineralization. Bones become weak, and vulnerable to fractures. X-ray findings are pseudo-fractures. Effects vertebral bodies and femoral necks. 12 marker enzymes used for clinical diagnosis Laboratory findings in Osteomalacia: Low levels of Vitamin D Increased levels of PTH Calcium will be low or normal Phosphorus will be low Elevated alkaline phosphatase 13  Vitamin D deficiency impairs mineralization of bones Inadequate substrate for 1α-hydroxylase and insufficient levels of calcitriol (1 and 2) Decreased calcium and phosphate absorption (3) Decreased plasma calcium and phosphate levels (4) Low serum calcium cause elevation of PTH secretion (5) Elevated PTH increases mobilization of calcium and phosphate from bones (6a) Elevated PTH increases the reabsorption of calcium from kidney, so the calcium excretion is decreased (6b) Elevated PTH increases urinary excretion of phosphate With VitD deficiency: normal plasma calcium may be restored but, hypophosphatemia persists. Hypophosphatemia impairs mineralization of bones (7) 14  Components of Bone 1. Bone matrix § Organic components: - Type I collagen - Calcium-binding glycoproteins Osteocalcin Osteonectin Form the non-mineralized matrix known as osteoid § Inorganic components - Crystals of calcium and phosphorous Hydroxyapatite (Calcium apatite) Ca10(PO4)6(OH)2 2. Bone cells o Osteoblasts o Osteoclasts o Osteocytes 15 Functions of PTH GI tract: increases absorption of calcium and phosphate from intestine Kidneys: promotes reabsorption of calcium in the kidney (enhances calcium retention) enhances excretion of phosphate in the urine stimulates calcitriol biosynthesis by activating 1α-hydroxylase enzyme in the kidney. Bone: activates osteoclasts and increases bone degradation (demineralization) promotes the mobilization of calcium from the bones (resorption) 16  Osteoporosis Osteoporosis is a condition in which bone resorption overweighs bone formation Decrease in both bone mineral and bone matrix – Bone composition is normal but overall bone mass decreased. – Decreased amount of bone causing appear “porous” Decreased estrogen, vitamin D, and calcium are often the principal causes Risk factors: gender, race, genetics (Estrogen receptor gene, Type I collagen gene, Vitamin D receptor (VDR) gene 17  Vitamin A Retinol, Retinal, Retinoic Acid The parent compound of vitamin A is retinol, which can be further converted in the body to retinal and retinoic acid. Retinal and retinoic acid can also be produced from β-carotene, which is found in fruits and vegetables and functions as an antioxidant. β-carotene is cleaved in the intestine to yield two molecules of retinal. 18  11-cis form of retinal is visual pigment of rhodopsin in the rod cells Absorption of light by rhodopsin causes isomerization of 11-cis retinal to 11-trans retinal 11-trans retinal activates rhodopsin, a G-protein coupled receptor. Activated rhodopsin activates the G-protein transducin through the association with GTP. The GTP-bound transducin activates the phosphodiesterase enzyme, which hydrolyzes cGMP, thus decreases the intracellular cGMP concentration. A decrease in cGMP closes the sodium channels, which hyperpolarizes the membranes. This hyperpolarization of the rod cell membrane inhibits the rate of glutamate release thus initiates signal to brain via optic nerve 19  In the dark, cGMP increases. Increased cGMP partially depolarizes the rod cells. The partial depolarization causes continuous release of glutamate (excitatory neurotransmitter; sends signals between nerve cells) After adaption to dark, eye can detect a single photon Therefore, vitamin A deficiency reduces the amount of rhodopsin in the retina may result in reduced photosensitivity, or (increasing the visual threshold) Dark adaptation progressively decreases. 20  Retinoic acid is a gene regulator regulates the expression of genes that affect growth, development, and differentiation of tissues. retinoic acid binds to retinoic acid receptors and retinoid X receptors in the nucleus Retinoid X receptors bind and form dimers with either the vitamin D receptor or the thyroid receptors. Retinoic acid promotes growth and differentiation of epithelial cells and mucus secretion from columnar epithelial cells 21  Deficiency of Vitamin A Deficiency of retinal night blindness prolonged deficiency leading to irreversible loss of visual cells Deficiency of retinoic acid impairs the functions of vitamin D and thyroid hormones, leads to a decrease in the growth rate in children as bone development is slowed, and can also affect spermatogenesis in males metaplasia of the corneal epithelium, xerophthalmia, a pathologic dryness of the conjunctiva and cornea The eye loses its mucus secreting cells and becomes keratinized squamous metaplasia: columnar epithelial cells are transformed into keratinized squamous epithelia. 22  Excess of vitamin A can be teratogenic during pregnancy retinoic acid functions as a gene regulator, either deficiency or excess of vitamin A can be teratogenic, which could result in significant congenital malformations to the developing fetus. Retinol and its precursor are used as dietary supplements Retinoic acid is useful in dermatology – Acne, psoriasis, skin aging can be treated with topical application of retinoic acid. – Severe recalcitrant cystic acne can be treated with oral administration of 11-cis retinoic acid. 23  Vitamin E is an antioxidant α-tocopherol is the most potent vit E. Antioxidant and scavenger of free radicals. Fat malabsorption may lead to vitamin E deficiency Deficiency may cause hemolytic anemia Vit E has a reputation for reducing the risk of cancer, coronary heart disease, and age-related degenerative diseases. 24 Lipid free radicals (L ) and lipid peroxides: Major contribution to ROS-induced injury. free-radical chain reaction: A. Initiation: OH attacks to polyunsaturated lipid on the membrane and extracts H, causes the formation of L B. Propagation: L reacts with O2 to form lipid peroxy radical (LOO ) and lipid peroxide (LOOH) C. Degradation: Lipid peroxides are very unstable and degrades easily This causes disruption of membrane integrity 25 Vitamin E (α-tocopherol) is antioxidant: Lipid-soluble, protects against lipid peroxidation in membranes Nonenzymatic terminator of free-radical chain reaction Vit E has a reputation for reducing the risk of cancer, coronary heart disease, and age-related degenerative diseases. Vitamin C can donate e- to VitEOX to regenerate Vitamin E (VitEred) 26  Vitamin K The dietary form of vitamin K is found in leafy vegetables and is known as phytomenadione, or K1. The active form of the vitamin K (menaquinones also known as K2) is produced by bacteria of the intestinal flora. 27  Vitamin K is required for blood clotting Vitamin K is the coenzyme of the glutamate carboxylase enzyme, which catalyzes the γ-carboxylation of glutamate residues of the coagulation factors II, VII, IX, X, and proteins C and S during their synthesis in hepatocytes, co-translational modification. This carboxylation of glutamate residues create calcium binding site in these blood clotting factors. 28  Deficiency of vitamin K presents with hemorrhagic conditions resulting from decreased formation of γ-carboxyglutamate residues on the blood clothing factors Glutamate carboxylase activity decreases --- clotting factors cannot function leads to a non-functional coagulation pathway. Causes increased prothrombin time and easy bruising. 29  Causes of Vitamin K Deficiency Vitamin K is not stored to any great extent, therefore in acute fat malabsorption, it is the first fat soluble vitamin to be deficient. Vitamin K deficiency is most common in newborns due to insufficient intestinal bacteria Abnormal bleeding diagnosed as hemorrhagic disease of the newborn. Vitamin K deficiency is also associated with long-term broad spectrum antibiotic therapy 30 Vitamin K antagonists: warfarin and dicumarol can be used as anticoagulant therapy in individuals who are at high risk for thrombotic events These drugs compete with vitamin K for binding to the glutamate carboxylase enzyme. Therefore, these drugs inhibit (antagonize) the glutamate carboxylase enzyme. γ-carboxylation of the blood clotting factors are decreased so; function of blood clotting pathway is compromised. 31