Chylomicron vitamin

Hypolipoproteinemias Abetaiipoproteinemia No chylomicrons, VLDL, or LDL are formed because of defect in the loading of apo B with lipid. Rare blood acylglycerols low intestine and liver accumulate acylglycerols. Intestinal malabsorption. Early death avoidable by administration of large doses of fat-soluble vitamins, particularly vitamin E. 

The major lipid-soluble antioxidant primarily associated with lipid membranes is a-tocopherol (vitamin E). Circulating a-tocopherol is carried by chylomicrons, LDL and HDL and also has extracellular antioxidant capacities. As a chain-breaking antioxidant, it short circuits the propagation phase of lipid peroxidation because the peroxyl radical will react with a-tocopherol more rapidly than a polyunsaturated ffitty acid (Burton and Traber, 1990). The resulting a-tocopheryl radical reacts with a second peroxyl radical to form an inactive, nonradical complex. In vitro, ascorbate regenerates the tocopheryl radical into its native non-radical form (Burton and Traber, 1990). 

In the enterocyte, provitamin A carotenoids are immediately converted to vitamin A esters. Carotenoids, vitamin A esters, and other lipophilic compounds are packaged into chylomicrons, which are secreted into lymph and then into the bloodstream. Chylomicrons are attacked by endothelial lipoprotein lipases in the bloodstream, leading to chylomicron remnants, which are taken up by the liver (van den Berg and others 2000). Carotenoids are exported from liver to various tissues by lipoproteins. Carotenes (such as (3-carotene and lycopene) are transported by low-density lipoproteins (LDL) and very low-density lipoproteins (VLDL), whereas xanthophylls (such as lutein, zeax-anthin, and (3-cryptoxanthin) are transported by high-density lipoproteins (HDL) and LDL (Furr and Clark 1997). 

The overall metabolism of vitamin A in the body is regulated by esterases. Dietary retinyl esters are hydrolyzed enzymatically in the intestinal lumen, and free retinol enters the enterocyte, where it is re-esterified. The resulting esters are then packed into chylomicrons delivered via the lymphatic system to the liver, where they are again hydrolyzed and re-esterified for storage. Prior to mobilization from the liver, the retinyl esters are hydrolyzed, and free retinol is complexed with the retinol-binding protein for secretion from the liver [101]. Different esterases are involved in this sequence. Hydrolysis of dietary retinyl esters in the lumen is catalyzed by pancreatic sterol esterase (steryl-ester acylhydrolase, cholesterol esterase, EC 3.1.1.13) [102], A bile salt independent retinyl-palmitate esterase (EC 3.1.1.21) located in the liver cell plasma hydrolyzes retinyl esters delivered to the liver by chylomicrons. Another neutral retinyl ester hydrolase has been found in the nuclear and cytosolic fractions of liver homogenates. This enzyme is stimulated by bile salts and has properties nearly identical to those observed for... 

Deficiency of vitamin E is rare it can occur from abnormalities in lipid absorption as well as dietary deficiency. Its deficiency affects the muscular system, causing dystrophy and paralysis and, if the heart is affected, death by myocardial failure. This is probably caused by demyelin-ation of axons due to oxidative damage. Vitamin E is incorporated into chylomicrons within the enterocyte, so that its uptake into cells requires the activity of lipoprotein lipase. 

The food components resorbed by the epithelial cells of the intestinal wall in the region of the jejunum and ileum are transported directly to the liver via the portal vein. Fats, cholesterol, and lipid-soluble vitamins are exceptions. These are first released by the enterocytes in the form of chylomicrons (see p. 278) into the lymph system, and only reach the blood via the thoracic duct. 

In the body retinol can also be made from the vitamin precursor carotene. Vegetables like carrots, broccoli, spinach and sweet potatoes are rich sources of carotene. Conversion to retinol can take place in the intestine after which retinyl esters are formed by esterifying retinol to long chain fats. These are then absorbed into chylomicrons. Some of the absorbed vitamin A is transported by chylomicrons to extra-hepatic tissues but most goes to the liver where the vitamin is stored as retinyl palmitate in stellate cells. Vitamin A is released from the liver coupled to the retinol-binding protein in plasma. 

Substantial evidence indicates that high plasma levels of lipoprotein remnants and LDL are atherogenic, while high levels of HDL are atheroprotective. Therefore, the class of lipoproteins that is increased or decreased will determine the clinical feature of a patient. Besides the influence on atherosclerosis, high levels of chylomicrons lead to acute pancreatitis, while markedly decreased levels of VLDL and LDL lead to retinal and neurologic disease, probably due to vitamin E deficiency. 

In chylomicron retention disease (Anderson s disease) the secretory defect is restricted to intestinal apoB-containing lipoproteins (i.e., chylomicrons). This very rare recessively inherited disorder results from defects in a GTPase, Sarlb, which plays a critical role in the intracellular assembly and trafficking of chylomicrons. The affected patients present with fat malabsorption resulting in steatorrhea and deficiency of fat-soluble vitamins [46, 52, 54]. 

Chylomicrons are assembled in intestinal mucosal cells and cany dietary triacylglycerol, cholesterol, fat-soluble vitamins, and cholesteryl esters (plus additional lipids made in these cells) to the peripheral tissues (Figure 18.16). 

The mixture of lipids moves to the endoplasmic reticulum, where fatty acyl CoA synthetase converts free fatty acids into their activated CoA derivatives. Fatty acyl CoAs are then used to produce triacylglycerols, cholesteryl esters, and phospholipids. These, together with the fat-soluble vitamins (A, D, E, and K) and a single protein (apolipoprotein B-48), form a chylomicron, which is secreted into the lymphatic system and carried to the blood. 

In the intestinal mucosal cells, /3-carotene is cleaved via an oxygenase (an enzyme that introduces molecular 02 into organic compounds) to frans-retinal (aldehyde form of trans-retinol, as shown in Table 6.2), which in turn is reduced to frans-retinol, vitamin Av Retinol is then esterified with a fatty acid, becomes incorporated into chylomicrons, and eventually enters the liver, where it is stored in the ester form until it is required elsewhere in the organism. The ester is then hydrolyzed, and vitamin Ax is transported to its target tissue bound to retinol-binding protein (RBP). Since RBP has a molecular weight of only 20,000 and would be easily cleared by the kidneys, it is associated in the bloodstream with another plasma protein, prealbumin. 

Abetalipoproteinemia (ABL) is a rare, autosomal recessive disease first described by Bassen and Kornsweig in 1950. It is characterized by the absence of plasma apoB lipoproteins, fat-soluble vitamin deficiencies (A, E, and K), and the presence of acanthocytosis (Table 27-1). Other signs include fat malabsorption presenting as steatorrhea, flatus, abdominal discomfort, and progressive ataxic neuropathy. The key diagnostic feature is an extremely low plasma total cholesterol and absence of all apoB lipoproteins (chylomicrons, VLDL, and LDL). 

ABL) recessive lipoproteins particle fat-soluble vitamin deficiencies, spinocerebellar disease, retinitis pigmentosa, acanthocytosis, galee blanche intestine, fatty liver apoB lipoproteins (chylomicrons, VLDL, and LDL)... 

Vitamin E, like neutral lipids, requires apoB lipoproteins at every stage of its transport (Fig. 27-2). Dietary vitamin E becomes emulsified in micelles produced during the digestive phase of lipid absorption and permeates the intestinal epithelium, similar to fatty acids and cholesterol. Uptake of vitamin E by enterocytes appears to be concentration dependent. Within intestinal cells, vitamin E is packaged into chylomicrons and secreted into lymph. During blood circulation of chylomicrons, some vitamin E may be released to the tissues as a consequence of partial lipolysis of these particles by endothelial cell-anchored lipoprotein lipase. The rest remains associated with chylomicron remnants. Remnant particles are mainly endocy-tosed by the liver and degraded, resulting in the release of fat-soluble vitamins. 

Uptake of vitamin A by intestinal cells is carrier mediated at low concentrations. If higher amounts are present, then it enters intestinal cells via diffusion. Like vitamin E, it also exploits chylomicrons as a vehicle to exit the enterocytes... 

Critical to vitamin D3 action is its further metabolic conversion to more active compounds (Figure 1.3). Via its transport by DBP, vitamin D3 accumulates in the liver [48]. In rats, as much as 60-80% of an injected or oral dose of vitamin D3 locates to the liver [49-51], Intestinal absorption of vitamin D3 is in association with the chylomicron fraction via the lymphatic system. Vitamin D3 is delivered to the liver in blood from the thoracic duct only a few hours post ingestion [44], A specific portion of hepatic vitamin D3 in the rat is converted to 25-OH-D3 by a 25-hydroxylase system in the endoplasmic reticulum of hepatocytes [52, 53]. This enzyme (Km 10"8 M) is regulated to an extent by 25-OH-D3 and its metabolites. Higher concentrations of vitamin D3 are handled by a second 25-hydroxylase located in liver mitochondria [54], This enzyme, also known as CYP27, 27-hydroxylates cholesterol and thus appears less discriminating than the microsomal 25-OHase which does not use cholesterol as substrate [55, 56]. In humans, however,... 

A small proportion of dietary retinol is oxidized to retuioic acid, which is absorbed into the portal circulation and bound to serum albumin. Some retinyl esters are also transferred into the portal circulation. Patients with abeta-lipoproteinemia, who are unable to synthesize chylomicrons, can nevertheless maintain adequate vitamin A status if they are provided with relatively high intakes of retinol. 

Although the major storage of vitamin A is in the liver (50% to 80% of the total body content), adipose tissue may contain 15% to 20% of total body vitamin A. Much of this is taken up from chylomicrons retinyl esters are hydrolyzed... 

The Relative Dose Response (RDR) Test The RDR test is a test of the ahUity of a dose of vitamin A to raise the plasma concentration of retinol several hours later, after chylomicrons have heen cleared from the circulation. What is being tested is the ahUity of the liver to release retinol into the circulation. In subjects who are retinol deficient, a test dose will produce a large increase in plasma retinol, because of the accumulation of apo-RBP in the liver in deficiency (Section 2.2.3). In those whose problem is due to lack of RBP, then little of the dose will be released into the circulation. An RDR greater than 20% indicates depletion of liver reserves of retinol to less than 70 /rmol per kg (Underwood, 1990). 

Synthetic ergocalciferol is used for enrichment and fortification of foods its metabolic fate is the same as that of dietary cholecalciferol. Except where there are known to be differences between the two vitamers, it is assumed that aU of the following discussion applies equally to ergocalciferol and cholecalciferol. There are few rich dietary sources of vitamin D, and the major source is usually photosynthesis in the skin. Dietary vitamin D is absorbed in chylomicrons and taken up rapidly by the liver as chylomicron remnants are cleared from... 

Because vitamin E is transported in lipoproteins secreted hy the liver, the plasma concentration depends to a great extent on total plasma lipids. Erythrocytes may also he important in transport, because there is a relatively large amount of the vitamin in erythrocyte membranes, and this is in rapid equilibrium with plasma vitamin E. There are two mechanisms for tissue uptake of the vitamin. Lipoprotein lipase releases the vitamin by hydrolyzing the tri-acylglycerol in chylomicrons and VLDL, whereas separately there is receptor-mediated uptake of LDL-bound vitamin E. Studies in knockout mice suggest that the main mechanism for tissue uptake of vitamin E from plasma lipoproteins is byway of the class B scavenger receptor (Mardones et al., 2002). 

In both groups of patients, the only source of vitamin E for peripheral tissues will be recently ingested vitamin E in chylomicrons. They develop cerebellar ataxia, axonal degeneration of sensory neurons, skeletal myopatby, and pigmented retinopatby similar to those seen in experimental animals. 

Phylloquinone is absorbed in the proximal small intestine, by an energy-dependent mechanism, and is incorporated into chylomicrons. Estrogens increase phylloquinone absorption in both male and female animals, and male animals are more susceptible to dietary vitamin K deprivation than females (loUy et al., 1977). Even after an overnight fast, about half the plasma vitamin K is present in chylomicron remnants, and only a quarter in low-density lipoprotein. The plasma concentration of phylloquinone is associated with genetic variants of apoprotein E, which determines the binding of chylomicron remnants to the liver lipoprotein receptor (Kohlmeier et al., 1996). 

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