Cholesterols transport form

The main transport form of lipids in the cir culation. They are spherical macromolecules of 10-1200 nm diameter-composed of a core of neutral lipids (mostly cholesterol ester and triglycerides) surrounded by an amphipathic shell of polar phospholipids and cholesterol. Embedded in the shell of lipoproteins are apolipoproteins that are essential for assembly of theparticles in tissues that secrete lipoproteins, and for their recognition by target cells. 

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. 

Cholesterol, a polycyclic alcohol [Fig. 3(1)] is present in all animal tissues. It is a major constituent of cellular membranes, where it contributes to the fluidity of the membrane. The storage and transport forms of cholesterol are its esters with fatty acids. 

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]. 

Another receptor, LXR (Liver X receptor), also exists in alpha and beta forms, and acts as a receptor for cholesterol and its degradation products, which accumulate when cholesterol levels are high. LXRs are expressed in the liver and lower digestive tract, where they regulate cholesterol and bile-acid homeostasis. LXR-beta activates reverse cholesterol transport from the periphery to the liver. LXR-alpha, which is found in the liver, promotes catabolism in the liver and drives catabolism of cholesterol to BAs. Its activation in the liver increases... 

Cholesterol is present in all animal tissues, and particularly in neural tissue. It is a major constituent of cellular membranes, in which it regulates fluidity (see p. 216). The storage and transport forms of cholesterol are its esters with fatty acids. In lipoproteins, cholesterol and its fatty acid esters are associated with other lipids (see p.278). Cholesterol is a constituent of the bile and is therefore found in many gallstones. Its biosynthesis, metabolism, and transport are discussed elsewhere (see pp. 172, 312). 

The HDLs also originate in the liver. They return the excess cholesterol formed in the tissues to the liver. While it is being transported, cholesterol is acylated by lecithin cholesterol acyltransferase (LCAT). The cholesterol esters formed are no longer amphipathic and can be transported in the core of the lipoproteins. In addition, HDLs promote chylomicron and VLDL turnover by exchanging lipids and apoproteins with them (see above). 

Eckardstein A von, Huang Y, Wu S, Funke H, Noseda G, Assmann G (1995) Reverse cholesterol transport in plasma of patients with different forms of familial HDL deficiency. Arterioscler Thromb Vase Biol 15 691-703... 

Cholesterol makes up 17% of myelin and is present in plasma membranes. However, it usually does not occur in bacteria and is present only in trace amounts in mitochondria. Related sterols are present in plant membranes. Esters of sterols occur as transport forms but are not found in membranes. Membrane bilayers, likewise, contain little or no triacylglycerols, the latter being found largely as droplets in the cytoplasm. 

The body contains sulfate esters of cholesterol and other sterols,245 sometimes in quite high concentrations relative to those of unesterified steroids. These esters are presumably soluble transport forms. They... 

Clinical measurements of total cholesterol in serum or plasma detect cholesterol esters in addition to cholesterol. Between 60 and 70% of the cholesterol transported in blood is in an esterified form, where the /3-3-OH group on the steroid skeleton is covalently linked to a naturally occurring... 

Unlike fatty acids, cholesterol is not degraded to yield energy. Instead excess cholesterol is removed from tissues by HDL for delivery to the liver from which it is excreted in the form of bile salts into the intestine. The transfer of cholesterol from extrahepatic tissues to the liver is called reverse cholesterol transport. When HDL is secreted into the plasma from the liver, it has a discoidal shape and is almost devoid of cholesteryl ester. These newly formed HDL particles are good acceptors for cholesterol in the plasma membranes of cells and are converted into spherical particles by the accumulation of cholesteryl ester. The cholesteryl ester is derived from a reaction between cholesterol and phosphatidylcholine on the surface of the HDL particle catalyzed by lecithimcholesterol acyltransferase (LCAT) (fig. 20.17). LCAT is associated with FIDL in plasma and is activated by apoprotein A-I, a component of HDL (see table 20.3). Associated with the LCAT-HDL complex is cholesteryl ester transfer protein, which catalyzes the transfer of cholesteryl esters from HDL to VLDL or LDL. In the steady state, cholesteryl esters that are synthesized by LCAT are transferred to LDL and VLDL and are catabolized as noted earlier. The HDL particles themselves turn over, but how they are degraded is not firmly established. 

The cholesterol-lowering properties of dietary plant sterols have been known for decades (Best et al., 1954 Peterson, 1951 Poliak, 1953), due specifically to reductions in cholesterol absorption. Inverse correlations between plant sterol intake and cholesterol absorption have been reported in animals (Carr et al., 2002 Ntanios and Jones, 1999) and humans (Ellegard et al., 2000). The exact mechanism by which plant sterols inhibit cholesterol absorption is unclear, and several mechanisms of action have been proposed, including (1) competition with cholesterol for solubilization in micelles within the intestinal lumen, (2) cocrystallization with cholesterol to form insoluble crystals, (3) interaction with digestive enzymes, and (4) regulation of intestinal transporters of cholesterol. 

ABCA1 mediates the first step in the energy-dependent efflux of cholesterol from the cell to form HDL for reverse cholesterol transport (Fig. 15-2). While all tissues in the body can synthesize cholesterol, only the liver and steroidogenic tissues can metabolize it. Surplus cholesterol in cells of the peripheral tissues is transported to the liver for either redistribution to other cells or for excretion either as free cholesterol or as a bile salt after conversion in the liver. Therefore, this reverse cholesterol transport system plays a pivotal role in cholesterol homeostasis with HDL as one of the key players. 

Acetyl CoA. The major sources of this activated two-carbon unit are the oxidative decarboxylation of pyruvate and the P-oxidation of fatty acids (see Figure 30.11). Acetyl CoA is also derived from ketogenic amino acids. The fate of acetyl CoA, in contrast with that of many molecules in metabolism, is quite restricted. The acetyl unit can be completely oxidized to CO2 by the citric acid cycle. Alternatively, 3-hydroxy-3-methylglutaryl CoA can be formed from three molecules of acetyl CoA. This six-carbon unit is a precursor of cholesterol and of ketone bodies, which are transport forms of acetyl units released from the liver for use by some peripheral tissues. A third major fate of acetyl CoA is its export to the cytosol in the form of citrate for the synthesis of fatty acids. 

A cholesterol ester forms In the liver of rats given an oral dose (250 mg/kg for seven days) of the hypolipidemic drug l-(4-carboxyphenoxy)-10-(4-chlorophenoxy)decane ( 2J ). This xenobiotic cholesterol ester represented about 11% of the total lipid In the liver and was neither further metabolized nor transported by lipoproteins. An additional 1% of the total liver lipids consisted of hybrid trlacylglycerols containing this xenobiotic. The authors of this work suggest that the hypocholesterolemlc activity of the drug In rats results from hepatic accumulation of the xenobiotic cholesterol ester which appears to promote the hydrolysis of natural cholesterol esters and thereby facilitate clearance of low-density lipoproteins. 

Lipids may be polar or nonpolar (amphipathic). Polar lipids have limited solubility in water because they are amphipathic, i.e., they possess hydrophilic and hydro-phobic regions in the same molecule. Major polar lipids include fatty acids, cholesterol, glycerophosphatides, and glycosphingolipids. Very short chain fatty acids and ketone bodies are readily soluble in water. Nonpolar lipids serve principally as storage and transport forms of lipid and include triacylglycerols (also called triglycerides) and cholesteryl esters. 

Plasma contains several apolipoproteins, involved in lipid and cholesterol transport. Several have been reported to be glycosylated in low amounts including apoB, apoE and apoC-llI [26]. ApoB contains about 2-2.5% carbohydrate as complex-type N-glycan whereas apoE appears to contain O-linked glycan [27]. ApoE is synthesized in sialylated form but in plasma it is 80% desialylated. 

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