Vitamin A: metabolism Domina Petric, MD

Absorption of vitamin A 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Absorption of retinoids Most of the preformed vitamin A in the diet is in the form of retinyl esters. Retinyl esters are hydrolyzed in the lumen of the small intestine to yield retinol. This step is catalyzed by hydrolases produced by the pancreas and situated on the mucosal brush border or intrinsic to the brush border itself. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Absorption of retinoids The retinyl esters, as well as the carotenoids, are hydrophobic and, thus, depend on micellar solubilization for their dispersion in the aqueous environment of the small intestinal lumen. Vitamin A is poorly utilized from low-fat diets! The micellar solubilization of vitamin A facilitates access of soluble hydrolytic enzymes to their substrates. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Absorption of retinoids The overall absorption of retinol from retinyl esters appears to be fairly high (about 75%). This process appears to be minimally affected by the level and type of dietary fat, although the absorption is appreciably less efficient at very high vitamin A doses . 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Absorption of retinoids Vitamin A can also be absorbed via non lymphatic pathways. In mammals, the portal system may be an important alternative route of vitamin A absorption when the normal lymphatic pathway is blocked. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Absorption of carotenoids The major sources of vitamin A activity for most populations are the provitamin A carotenoids. The carotenoids appear to be absorbed in the distal small intestine by micelle-dependent passive diffusion. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Carotenoid metabolism linked to absorption Some carotenoids can be provitamins A because they can be metabolized to yield retinal due to the action of retinal-forming carotene dioxygenases. Most of this bioconversion occurs via the central cleavage of the polyene moiety by a predominantly cytosolic enzyme, β-carotene 15,15′-dioxygenase, found in the intestinal mucosa, liver and corpus luteum. The enzyme requires iron as a cofactor. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Retinoid metabolism linked to absorption Retinal produced by at least the central cleavage step is reduced in the intestinal mucosa to retinol. This step is catalyzed by another enzyme, retinaldehyde reductase, which is also found in the liver and eye. The reduction requires a reduced pyridine nucleotide (NADH/NADPH) as a cofactor. This step can be catalyzed by a short-chain alcohol dehydrogenase/aldehyde reductase. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Mucosal metabolism of retinol Retinol, formed either from the hydrolysis of dietary retinyl esters or from the reduction of retinal cleaved from β-carotene, is absorbed by facilitated diffusion via a specific transporter. Then, retinol is quickly re-esterified with long- chain fatty acids in the intestinal mucosa. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Mucosal metabolism of retinol Vitamin A is transported to the liver mainly (80 to 90% of a retinol dose) in the form of retinyl esters. The composition of lymph retinyl esters is independent of the fatty acid composition of the most recent meal. Retinyl palmitate typically comprises about half of the total esters. Retinyl stearate comprises about a quarter. Retinyl oleate and retinyl linoleate are present in small amounts. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Two pathways for the enzymatic reesterification of retinol are: A low-affinity route involves uncomplexed retinol. It is catalyzed by acyl-CoA: retinol acyltransferase. A high-affinity route involves retinol complexed with a specific binding protein, cellular retinol- binding protein type II. It is catalyzed by lecithin–retinol acyltransferase. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Vitamin A transport II. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Retinyl esters Retinyl esters are secreted from the intestinal mucosal cells in the hydrophobic cores of chylomicron particles, by which absorbed vitamin A is transported to the liver through the lymphatic circulation, ultimately entering the plasma compartment through the thoracic duct. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Transport of carotenoids Carotenoids that are not metabolized at the intestinal mucosa are transported from that organ by chylomicra via the lymphatic circulation to the liver, where they are transferred to lipoproteins. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Transport of carotenoids The hydrocarbon carotenoids are transported primarily in low-density lipoproteins (LDLs). The more polar carotenoids are transported in a more evenly distributed manner among LDLs and high-density lipoproteins (HDLs). 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Transport of carotenoids β-carotene is retained by the chylomicron remnants to be internalized by the liver for subsequent secretion in very low density lipoproteins (VLDLs). 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Impact of abetalipoproteinemia The absorption of vitamin A (as well as the other fat soluble vitamins) is a particular problem in patients with abetalipoproteinemia. These patients lack apo B and can not synthesize any of the apo B-containing lipoproteins: LDLs, VLDLs, chylomicra. Having no chylomicra, they show hypolipidemia and low plasma vitamin A levels. When given oral vitamin A supplementation, their plasma levels are normal. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Storage of vitamin A in the liver Newly absorbed retinyl esters are taken up by the liver in association with chylomicron remnants by receptor-mediated endocytosis on the part of liver parenchymal cells. Within those cells, remnants are degraded by lysosomal enzymes. Retinol can be transferred from the parenchymal cells to stellate cells, where it is re-esterified. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Retinyl ester hydrolysis Vitamin A is mobilized as retinol from the liver by hydrolysis of hepatic retinyl esters. This mobilization accounts for about 55% of the retinol discharged to the plasma (the balance comes from recycling from extrahepatic tissues). The retinyl ester hydrolase involved in this process shows extreme variation between individuals. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Retinol-binding protein Once mobilized from liver stores, retinol is transported to peripheral tissues by means of a specific carrier protein, plasma retinol-binding protein (RBP). 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Transport of retinoids The transport, storage, and metabolism of the retinoids involve their binding to several other binding proteins, such as cellular retinol-binding protein types I and II, and cellular retinoic acid-binding protein types I and II. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Cellular uptake of retinol Due to their hydrophobic character, the plasma membranes do not present a barrier to retinol uptake. Retinol can enter target cells by nonspecific partitioning into the plasma membrane from RBP, but most of the vitamin appears to enter cells through specific RBP (receptor-mediated mechanisms). 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

The majority of retinol that leaves the plasma appears to be recycled. Retinol recycling The majority of retinol that leaves the plasma appears to be recycled. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Plasma retinol homeostasis In healthy individuals, plasma retinol is maintained within a narrow range: 40–50 mg/ml in adults. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Vitamin A in adipose tissue Appreciable amounts of vitamin A are stored in adipocytes: 15–20% of total body store. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Retinol is transferred from mother to infant through milk. Milk retinol Retinol is transferred from mother to infant through milk. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Metabolism of vitamin A III. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Metabolism of vitamin A The metabolism of vitamin A centers around the transport form, retinol, and the various routes of conversion available to it: esterification conjugation oxidation isomerization 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Excretion of vitamin A IV. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Excretion of vitamin A Vitamin A is excreted in various forms in both the urine and feces. Under normal physiological conditions, the efficiency of enteric absorption of vitamin A is high (80–95%), with 30–60% of the absorbed amount being deposited in esterified form in the liver. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.

Literature Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008. 9/18/2018 Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc. 2008.