Peripheral tissues, cholesterol transport

Profiling of plasma lipoproteins and serum lipids can often aid in the diagnosis of Tangier disease. There are four classes of lipoproteins (1) chylomicrons, which transport dietary cholesterol and triglycerides from the intestines to the tissues (2) very low-density lipoproteins (VLDL) and (3) low-density lipoproteins (LDL), both of which transport de novo synthesized cholesterol and triglyceride from the liver to the tissues and (4) high-density lipoproteins (HDL), which mediate reverse cholesterol transport, a process in which excess cholesterol from peripheral tissues is transported to the liver. 

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. 

Cholesterol is packaged in chylomicrons in the intestine and in very-low-den-sity lipoprotein (VLDL) in the liver. It is transported in the blood in these lipoprotein particles, which also transport triacylglycerols. the triacylglycerols of the blood lipoproteins are digested by lipoprotein lipase, chylomicrons are converted to chylomicron remnants, and VTDT is converted to intermediate-density lipoprotein (IDL) and subsequently to low-density lipoprotein (LDL). These products return to the liver, where they bind to receptors in cell membranes and are taken up by endocytosis and digested by lysosomal enzymes. LDL is also endocy-tosed by nonhepatic (peripheral) tissues. Cholesterol and other products of lysosomal digestion are released into the cellular pools. The liver uses this recycled cholesterol, and the cholesterol that is synthesized from acetyl CoA, to produce VLDL and to synthesize bile salts. 

Much of the endogenous lipid that is eventually used by peripheral tissues is transported in the form of water-soluble ketone bodies, the two most important being jS-hydroxybutyrate and acetoacetate. The metabolic pathway of ketone body formation and its relationship to cholesterol biosynthesis is shown in Fig. 4.10. Four enzymes are Involved in the formation of ketone bodies, namely acetyl-CoA transferase (also known as thiolase), hydroxymethylglutaryl-CoA synthase (HMG-CoA synthase), hydroxymethyl-glutaryl-CoA lyase (HMG-CoA lyase) and jS-hy-droxybutyrate dehydrogenase. Tbe last of these catalyses the interconversion of the two principal ketone bodies. All four enzymes are present in liver, the principal site of ketone body formation. Acyl-CoAs are unable to pass through the plasmalemma, and HMG-CoA lyase thus controls the release of ketone... 

HDL 5 20 25 50 Precursor secreted by liver, plasma particle probably derived from action of LPL and LCAT Donor/acceptor of protein to/from other lipoproteins. Transport of peripheral tissue cholesterol to liver... 

Lipoprotein metabolism is the process by which hydrophobic lipids, namely triglycerides and cholesterol, are transported within the interstitial fluid and plasma. It includes the transport of energy in the form of triglycerides from intestine and liver to muscles and adipose, as well as the transport of cholesterol both from intestine and liver to peripheral tissues, as well as from peripheral tissues back to the liver. 

Contrary to LDL, high-density lipoproteins (HDL) prevent atherosclerosis, and therefore, their plasma levels inversely correlate with the risk of developing coronary artery disease. HDL antiatherogenic activity is apparently due to the removal of cholesterol from peripheral tissues and its transport to the liver for excretion. In addition, HDL acts as antioxidants, inhibiting copper- or endothelial cell-induced LDL oxidation [180], It was found that HDL lipids are oxidized easier than LDL lipids by peroxyl radicals [181]. HDL also protects LDL by the reduction of cholesteryl ester hydroperoxides to corresponding hydroperoxides. During this process, HDL specific methionine residues in apolipoproteins AI and All are oxidized [182]. 

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]. 

High density lipoprotein (HDL) 50 1-5 20 30 45-55 Transport of cholesterol from peripheral tissues to the liver for catabolism... 

The apoproteins of HDL are secreted by the liver and intestine. Much of the lipid comes from the surface monolayers of chylomicrons and VLDL during lipolysis. HDL also acquire cholesterol from peripheral tissues in a pathway that protects the cholesterol homeostasis of cells. In this process, free cholesterol is transported from the cell membrane by a transporter protein, ABCA1, acquired by a small particle termed prebeta-1 HDL, and then esterified by lecithin cholesterol acyltransferase (LCAT), leading to the formation of larger HDL species. The cholesteryl esters are transferred to VLDL, IDL, LDL, and chylomicron remnants with the aid of cholesteryl ester transfer protein (CETP). Much of the cholesteryl ester thus transferred is ultimately delivered to the liver by endocytosis of the acceptor lipoproteins. HDL can also deliver cholesteryl esters directly to the liver via a docking receptor (scavenger receptor, SR-BI) that does not endocytose the lipoproteins. 

This sequence of reactions is incompletely understood but involves numerous oxidations of carbon groups, for example, the conversion of methyl groups to carboxylic acids, followed by decarboxylation. The end product, cholesterol, is the precursor to cholesterol esters in the liver and is transported to the peripheral tissues where it is a precursor to membranes (all cells), bile salts (liver), steroid hormones (adrenals and reproductive tissues), and vitamin D (skin, then liver, and finally kidney). 

It should be noted that in addition to the GABA(A)-R benzodiazepine-binding sites or central benzodiazepine Rs (CBZ-Rs) there are peripheral benzodiazepine Rs (PBZ-Rs) associated with the outer membrane of mitochondria in glial cells and cells of peripheral tissue and which are involved in cholesterol transport and hence in regulation of steroid hormone synthesis. The GABA(B)-Rs are metabotropic and coupled via heterotrimeric G proteins to Ca2+ and K+ channels (Chapter 5). The psychotropic GABA breakdown product y-hydroxybutyrate (GHB) also acts via heterodimeric G protein-linked receptors (see Chapter 5). 

HDL is synthesised and secreted from the liver and gut and aids the removal of cholesterol from peripheral tissues. It opposes the effects of LDL and protects against coronary heart disease. HDL is the substrate for LCAT, which converts the cholesterol in circulating plasma lipoproteins to cholesterol esters, which are then transferred to other lipoprotein particles. This is termed reverse cholesterol transport. Table... 

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. 

Cholesterol is then transported to peripheral tissues where, for example, it is converted to steroid hormones or used to form cell walls and... 

The quantity of cholesterol transported from the liver to peripheral tissues greatly exceeds its catabolism there and mechanisms exist to return cholesterol to the liver. Through this reverse transport, cholesterol is carried by high-density lipoprotein (HDL) from peripheral cells to the liver where it is taken up by a process involving hepatic lipase. Cholesterol in the plasma is also recycled to LDL and VLDL by cholesterol-ester transport protein (CETP). 

HDL, like LDL, is a cholesterol-rich particle, and is distinct from the other lipoprotein classes in that it does not contain apoB. HDL levels are inversely correlated with risk for atherosclerosis (Wilson et al., 1988). Nascent HDL particles are produced by direct synthesis (Hamilton, 1984), and excess surface remnants from chylomicrons and VLDL produced during the action of lipoprotein lipase (as noted above) enter the HDL density class. HDL appears to be involved in delivery of cholesterol to steroidogenic tissues as well as the removal of excess cholesterol from peripheral tissues and excretion from the system. This HDL-mediated removal of cholesterol has been termed reverse cholesterol transport (Glomset, 1968). Although apolipoproteins present in HDLs are cleared by the liver, the reverse cholesterol transport pathway has never been directly demonstrated. HDL can remove cholesterol from tissues, a process that may be partially mediated by interaction with a putative HDL receptor, with apoA-I as the ligand for that receptor (Oram el ai, 1983). The existence of an HDL receptor remains controversial saturable HDL binding may not be mediated by a specific apolipoprotein ligand and may not even be required for transfer of cholesterol from cells to... 

Chylomicrons and very-low-density lipoproteins (VLDL s) act primarily as carriers of triglycerides from the intestines to peripheral tissues, whereas LDL s and HDL s act as carriers of choiesteroi to and from the liver. Present evidence suggests that LDL s transport cholesterol as its... 

Low-density lipoproteins (LDL) Transport cholesterol and triglycerides from the liver to peripheral tissues and regulate the synthesis of cholesterol contribute to atherosclerotic plaque... 

HDL is antiatherogenic and removes cholesterol from peripheral cells and tissues for eventual transport to hepatocytes and excretion in the bile directly or after conversion into bile acids. The efflux of cholesterol from peripheral cells is mediated by the ATP-binding cassette (ABC) transporter protein (discussed later). The flux of cholesterol transport from extrahepatic tissues (e.g., blood vessel wall) toward liver for excretion is known as the reverse cholesterol transport pathway. In contrast, the forward cholesterol pathway involves the transport of cholesterol from liver to the peripheral cells and tissues via the VLDL IDL LDL pathway. It should be noted, however, that the liver plays a major role in the removal of these lipoproteins. Thus, the system of reverse cholesterol transport consisting of LCAT, CETP, apo D, and their carrier lipoproteins is critical for maintaining cellular cholesterol homeostasis. The role of CETP is exemplified in clinical studies involving patients with polymorphic... 

Role of HDL in peripheral cholesterol removal. Free cholesterol in plasma membranes of peripheral tissues is transferred to apo A-I containing pre-/ -HDL (nascent HDL), via an ATP-binding cassette transporter 1 (ABCl). Cholesterol is esterified by LCAT and stored in the core of the HDL particle. In the presence of suitable acceptor lipoproteins (VLDL or LDL), cholesteryl esters are transferred from HDL via apo D and CETP to the lower density lipoproteins, thereby shortening the half-life of plasma cholesterol since VLDL and LDL have a much faster turnover time than HDL. PL = Phospholipid. 

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