Cholesterols transport

Several classes of lipoproteins exist, characterized by the various amounts of triglycerides, cholesterol, phospholipids, and protein with which they are composed. The lipoproteins are commonly classified based on their density and are as follows chylomicrons, VLDLs, low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs). Individual lipoprotein class exerts differential physiological function in the body. 

Chylomicrons are the largest of the lipoproteins and have the lowest density at 0.95 g/ml. As mentioned earher, a major role of chylomicrons is to transport lipids originating from dietary sources from the small intestine to other tissues and ultimately to the liver. After triglycerides are deposited in peripheral tissues by the action of lipoprotein lipase, the chylomicron remnants are transferred to the hver, where they are endocytosed. As the remnant is hydrolytically degraded, the cholesterol released from the chylomicron regnlates the rate of biosynthesis of cholestraol in the liver. 

which have a density range of 0.95 to 1.006 g/ml, are produced in the liver and function as transporters for endogenons triglycerides and cholesterol to peripheral tissues. The primary apolipoprotein constitnents of VLDLs are apolipo-proteins B-lOO, Cs, and E. Apolipoprotein E present in VLDL plays an important role in plasma lipoprotein metabolism throngh its high binding affinity to cell surface EDL receptors, which could reduce plasma VLDL and LDL concentration as well as the atherosclerotic process.  

Of the hpoprotdns, HDLs contain the highest amonnt of protein and make np approximately 20 to 30% of the total semm cholesterol. Though numerous 

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The pathways of HDL metabolism and reverse cholesterol transport are complex (Fig. 3, [1]). HDL and its major apolipoprotein apoA-I are synthesized by both the intestine and the liver. A second major... 

Lipoprotein Metabolism. Figure 3 HDL metabolism and reverse cholesterol transport. 

Macrophage/athero- t Reverse cholesterol transport from foam cells l Progression of atherosclerosis... 

HDL concentrations vary reciprocally with plasma triacylglycerol concentrations and directly with the activity of lipoprotein lipase. This may be due to surplus surface constituents, eg, phospholipid and apo A-I being released during hydrolysis of chylomicrons and VLDL and contributing toward the formation of preP-HDL and discoidal HDL. HDLj concentrations are inversely related to the incidence of coronary atherosclerosis, possibly because they reflect the efficiency of reverse cholesterol transport. HDL, (HDLj) is found in... 

Four major groups of lipoproteins are recognized Chylomicrons transport lipids resulting from digestion and absorption. Very low density lipoproteins (VLDL) transport triacylglycerol from the liver. Low-density lipoproteins (LDL) deliver cholesterol to the tissues, and high-density lipoproteins (HDL) remove cholesterol from the tissues in the process known as reverse cholesterol transport. 

Figure 26-5. Factors affecting cholesterol balance at the cellular level. Reverse cholesterol transport may be initiated by pre 3 HDL binding to the ABC-1 transporter protein via apo A-l. Cholesterol is then moved out of the cell via the transporter, lipidating the HDL, and the larger particles then dissociate from the ABC-1 molecule. (C, cholesterol CE, cholesteryl ester PL, phospholipid ACAT, acyl-CoA cholesterol acyltransferase LCAT, lecithinicholesterol acyltransferase A-l, apolipoprotein A-l LDL, low-density lipoprotein VLDL, very low density lipoprotein.) LDL and HDL are not shown to scale.

Familial lecithimcholesterol acyltransferase (LCAT) deficiency Absence of LCAT leads to block in reverse cholesterol transport. HDL remains as nascent disks incapable of taking up and esterifying cholesterol. Plasma concentrations of cholesteryl esters and lysolecithin are low. Present is an abnormal LDL fraction, lipoprotein X, found also in patients with cholestasis. VLDL is abnormal ( 3-VLDL). 

Caco-2 cells and ezetimibe, a potent inhibitor of chloresterol absorption in humans, it was reported that (1) carotenoid transport was inhibited by ezetimibe up to 50% and the extent of that inhibition diminished with increasing polarity of the carotenoid molecule, (2) the inhibitory effects of ezetimibe and the antibody against SR-BI on P-carotene transport were additive, and (3) ezetimibe may interact physically with cholesterol transporters as previously suggested - and also down-regulate the gene expression of three surface receptors, SR-BI, NPCILI, and ABCAl. 

The hypothesis of the participation of those cholesterol transporters (NPCILI and ABCAl) in the carotenoid transport remains to be confirmed, especially at the in vivo human scale. If the mechanism by which carotenoids are transported through the intestinal epithelial membrane seems better understood, the mechanism of intracellular carotenoid transport is yet to be elucidated. The fatty acid binding protein (FABP) responsible for the intracellular transport of fatty acids was proposed earlier as a potential transporter for carotenoids. FABP would transport carotenoids from the epithelial cell membrane to the intracellular organelles such as the Golgi apparatus where CMs are formed and assembled, but no data have illustrated this hypothesis yet. 

Niacin (vitamin B3) has broad applications in the treatment of lipid disorders when used at higher doses than those used as a nutritional supplement. Niacin inhibits fatty acid release from adipose tissue and inhibits fatty acid and triglyceride production in liver cells. This results in an increased intracellular degradation of apolipoprotein B, and in turn, a reduction in the number of VLDL particles secreted (Fig. 9-4). The lower VLDL levels and the lower triglyceride content in these particles leads to an overall reduction in LDL cholesterol as well as a decrease in the number of small, dense LDL particles. Niacin also reduces the uptake of HDL-apolipoprotein A1 particles and increases uptake of cholesterol esters by the liver, thus improving the efficiency of reverse cholesterol transport between HDL particles and vascular tissue (Fig. 9-4). Niacin is indicated for patients with elevated triglycerides, low HDL cholesterol, and elevated LDL cholesterol.3... 

Bailey, KR, Ishida, BY, Duncan, KG, Kane, JP, and Schwartz, DM, 2004. Basal reverse cholesterol transport of retinal pigment epithelium cell digested photoreceptor outer segment lipids. Invest Ophthalmol Vis Sci 45, U721. 

The first study was conducted to determine whether carotenoids and cholesterol share common pathways (transporters) for their intestinal absorption (During et al., 2005). Differentiated Caco-2 cells on membranes were incubated (16 h) with a carotenoid (1 pmol/L) with or without ezetimibe (EZ Zetia, an inhibitor of cholesterol transport), and with or without antibodies against the receptors, cluster determinant 36 (CD36) and scavenger receptor class B, type I (SR-BI). Carotenoid transport in Caco-2 cells (cellular uptake + secretion) was decreased by EZ (lOmg/L) as follows P-C and a-C (50% inhibition) P-cryptoxanthin and LYC (20%) LUT ZEA (1 1) (7%). EZ reduced cholesterol transport by 31%, but not retinol transport. P-Carotene transport was also inhibited by anti-SR-BI, but not by anti-CD36. The inhibitory effects of EZ and anti-SR-BI on P-C transport... 

Alpy, F. and Tomasetto, C. 2006. MLN64 and MENTHO, two mediators of endosomal cholesterol transport. Biochem. Soc. Trans., 34(Pt 3) 343-345. 

Miller, W. L. 2007. Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter. Biochim. Biophys. Acta, 1771(6) 663-676. 

Sakudoh, T., Tsuchida, K., and Kataoka, H. 2005. BmStartl, a novel carotenoid-binding protein isoform from Bombyx mori, is orthologous to MLN64, a mammalian cholesterol transporter. Biochem. Biophys. Res. Commun., 336(4) 1125—1135. 

Apolipoprotein E (ApoE) A protein involved in cholesterol transport that has three major isoforms, one of which, ApoE4, significantly increases the risk of developing Alzheimer s disease. 

Apolipoprotein AI (apoAI) is the major apolipoprotein of HDL and plays an important role in the formation of mature HDL and the reverse cholesterol transport. HDL concentrations are largely determined by the rate of synthesis of apoAI in the liver. As a consequence deficiency of apoAI results in an almost complete absence of HDL and in accelerated atherosclerosis. In the promoter of the apoAI... 

The lipid compositions of plasma membranes, endoplasmic reticulum and Golgi membranes are distinct 26 Cholesterol transport and regulation in the central nervous system is distinct from that of peripheral tissues 26 In adult brain most cholesterol synthesis occurs in astrocytes 26 The astrocytic cholesterol supply to neurons is important for neuronal development and remodeling 27 The structure and roles of membrane microdomains (rafts) in cell membranes are under intensive study but many aspects are still unresolved 28... 

Cholesterol transport and regulation in the central nervous system is distinct from that of peripheral tissues. Blood-borne cholesterol is excluded from the CNS by the blood-brain barrier. Neurons express a form of cytochrome P-450, 46A, that oxidizes cholesterol to 24(S)-hydroxycholesterol [11] and may oxidize it further to 24,25 and 24,27-dihydroxy products [12]. In other tissues hydroxylation of the alkyl side chain of cholesterol at C22 or C27 is known to produce products that diffuse out of cells into the plasma circulation. Although the rate of cholesterol turnover in mature brain is relatively low, 24-hydroxylation may be a principal efflux path to the liver because it is not further oxidized in the CNS [10]. 

PXR CAR FXR LXR AhR 3A4 and others 2B, 2C, 3A4 7A 7A 1A1, 1A2, 1A6, 1B1, 2S1 Xenobiotic metabolism regulation, antioxidant Xenobiotic metabolism regulation Bile add metabolism and transport Reverse cholesterol transport and absorption Reproduction and development regulation... 

Gilroy DJ, Carpenter HM, Curtis LR. 1994. Chlordecone pretreatment alters [14C]chlordecone and [14C]cholesterol transport kinetics in the perfused rat liver. Fund Appl Toxicol 22 286-292. 

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