Cholesterol transport from tissue

HDL particles are able to transfer cholesterol from tissue cells to LDL particles. In this way, cholesterol is transported from tissues to the liver. 

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). 

Apolipoprotein (apo) A-I expression was demonstrated in porcine brain capillaries, suggesting an independent lipid metabolism inthebrain(151). Apo A-Iisthe major protein component of HDLs, which are responsible for reverse cholesterol transport from various tissues to the liver via the SR-BI receptor. Further research indicated that apo A-I was effluxed by porcine BCEC, whereas aortic endothelial cells did not. In addition, apo A-I-inducing compounds, such as cholesterol,... 

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... 

Fig. 8. A schematic diagram showing cellular processes known to require SCP2. The reactions in cholesterol biosynthesis and esterification have been shown for liver. The reactions involving cholesterol transport from cytoplasmic lipid inclusion droplets to mitochondria have been demonstrated in endocrine tissues. Choi and C. cholesterol ACAT, acyl-CoA cholesterol acyl transferase C.E., cholesterol ester SEH, sterol ester hydrolase (hormone-dependent) P-450s,, cytochrome P-450 cholesterol side-chain cleavage enzyme PREG, pregnenolone.

The evaluation of effects of dietary constituents on plasma lipid and lipoproteins requires selective measurements of individual lipoprotein classes. For example, the addition of cholesterol to the diet in the rat does not increase total plasma cholesterol levels in the present study a slight reduction in plasma cholesterol was in fact seen. However, the HDL cholesterol fraction was markedly reduced, and the VLDL and/or LDL cholesterol level must therefore have been increased. Extrapolation from data in humans would indicate that this shift in lipoprotein profile is disadvantageous from the atherogenic point of view. The increase in VLDL/ LDL cholesterol may readily be explained by the dietary load of cholesterol which is transported to peripheral tissues by these lipoprotein particles (J6). The reduction in HDL which are considered to be involved in cholesterol transport from peripheral tissues to the liver, is however an interesting but so far unexplained phenomenon. 

Niacin effectively raises high density lipoprotein (HDL) cholesterol levels. In the absence of HDL, peripheral tissues accumulate cholesterol, presumably due to lack of reverse cholesterol transport from peripheral tissues to the liver. Niacin inhibits the degradation of HDL protein by HepG2 cells, potentially by downregulating cell surface expression of the ATP synthase beta chain. 

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. 

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. 

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... 

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]. 

A high plasma concentration of LDL (usually measured as LDL-cholesterol) is a risk factor for the development of atheroma whereas a high concentration of HDL is an anti-risk factor for cardiovascular disease (CVD). Fundamental discoveries relating to cholesterol metabolism and the importance of the LDL receptor made by Nobel laureates Joseph Goldstein and Michael Brown led to an understanding of the role of LDL in atherosclerosis. The impact of HDL in reducing CVD risk is often explained by the removal of excess cholesterol from tissues and its return to the liver, a process known as reverse cholesterol transport. However, evidence from research by Gillian Cockerill and others shows that HDL has a fundamental anti-inflammatory role to play in cardioprotection. 

The liver synthesizes VLDL to transport triglycerides, vitamin E and, to a lesser extent, cholesterol from the hepatocytes to various tissues of the body. Initially, VLDL contain apolipoprotein B-100 (apoB-100), apoE, and the C-apolipoproteins, but receive additional apolipoproteins and cholesterol esters from HDL in the circulation. Following triglyceride hydrolysis by LPL, VLDL remnants, termed IDL, are formed... 

HDL may be taken up in the liver by receptor-mediated endocytosis, but at least some of the cholesterol in HDL is delivered to other tissues by a novel mechanism. HDL can bind to plasma membrane receptor proteins called SR-BI in hepatic and steroidogenic tissues such as the adrenal gland. These receptors mediate not endocytosis but a partial and selective transfer of cholesterol and other lipids in HDL into the cell. Depleted HDL then dissociates to recirculate in the bloodstream and extract more lipids from chylomicron and VLDL remnants. Depleted HDL can also pick up cholesterol stored in extrahepatic tissues and carry it to the liver, in reverse cholesterol transport pathways (Fig. 21-40). In one reverse transport path, interaction of nascent HDL with SR-BI receptors in cholesterol-rich cells triggers passive movement of cholesterol from the cell surface into HDL, which then carries it back to the liver. In a second pathway, apoA-I in depleted HDL in-... 

While the primary role of LDL appears to be the transport of esterified cholesterol to tissues, the high density lipoproteins (HDL) carry excess cholesterol away from most tissues to the liver 205 207 The apoA-I present in the HDL particle not only binds lipid but activates LCAT, which catalyzes formation of cholesteryl esters which migrate into the interior of the HDL and are carried to the liver. 

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 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. 

TG are derived directly from the diet and secreted from the intestines (primarily by way of the lymph) as CM and TRL or synthesized into VLDL in the liver. The net transport of TG is therefore from the intestines and the liver to skeletal and cardiac muscle or to adipose tissue for storage. Cholesterol is used for membrane synthesis and steroid production and is primarily synthesized in extrahepatic tissues. It is continuously transported between the liver, intestines, and extrahepatic tissues, but the net transport of cholesterol is from the extrahepatic tissues to the liver and intestines from where it is eliminated. 

FIG. 1 Schematic diagram of cholesterol transport in the tissues, with sites of action of the main drug affecting lipoprotein metabolism (C = cholesterol CE = cholesteryl ester TG = triglycerides MV A = mevalonate HMG-CoA reductase = 3-hydroxy-3-methyl-glutaryl-CoA reductase YLDL = very low density lipoproteins LDL = low density lipoproteins HDL = high density lipoproteins). (Reprinted from Rang et al (1999), with permission from Elsevier Science.)... 

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. 

Figure 5.6 General scheme of lipoprotein metabolism. Triacylglycerols and cholesterol are exported from the liver in VLDLs, containing apolipoprotein B-lOO they further acquire apo-C-I, II, III and apo-E from circulating HDL. Apo-C-II activates lipoprotein lipase to remove fatty acids from VLDLs. As triacylglycerols are removed, VLDLs transform to IDEs and finally LDLs. LDLs are the main vehicle for transfer of cholesterol to the tissues uptake of LDL occurs primarily in the liver through LDL-receptor-mediated endocytosis, which requires the presence of apo-B-100. HDLs are synthesised essentially devoid of cholesterol or triacylglycerol and provide a circulating source of apo-C-I, II and apo-E. HDLs gradually accumulate cholesteryl esters, eventually returning these to the liver, mediated by an apo-A-I receptor this is referred to as reverse cholesterol transport. ...

A proposed mechanism by which an exercise-induced increase in LCAT leads to an increase in HDL cholesterol is illustrated in figure 3. An increase in both Apo AI and LCAT activity in response to exercise could lead to Increased esterification of cholesterol in HDL and thereby allows for an increase in the transport of free cholesterol from tissues and other lipoproteins to nascent HDL, and enhanced formation of HDL2. While still speculative, this proposed mechanism deserves attention. 

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... 

---