Liver cholesterol transport

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... 

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... 

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... 

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]. 

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. 

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. 

ICAT (or PCAT, phosphatidylcholine-cholesterol acyltransferase) is an enzyme in the blood that is activated by apoA-1 on HDL. LCAT adds a fatty add to cholesterol, producing cholesterol esters, which dissolve in the core of the HDL, allowing HDL to transport cholesterol from the periphery to the liver. This process of reverse cholesterol transport is shown in Figure 1-15-7. 

The HDL may subsequently be picked up by the liver throu the apoE receptor or deliver cholesterol throi the scavenger receptor SR-Bl (reverse cholesterol transport firom the periphery to the liver). The HDL may also transfer the cholesterol to an IDL reforming a normal, unoxidized LDL particle. 

Fukumoto, H., Deng, A., Irizarry, M.C., Fitzgerald, M.L., Rebeck, G.W. (2002) Induction of the cholesterol transport ABCAl in central nervous system cells by liver X receptor agonists increases secreted AP levels. J. Biol. Chem., 277, 48508-48513. 

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... 

G. HDL particles have several functions, but among the most important is transport of excess cholesterol scavenged from the cell membranes back to the liver, a process called reverse cholesterol transport. 

Low HDL cholesterol (<35 mg/dL) is an independent risk factor for CHD. HDL appears to antagonize atherogenesis by at least two mechanisms. HDL can mobilize cholesterol from extrahepatic cells (such as arterial wall foam cells) and transport it to the liver for disposal (reverse cholesterol transport) HDL also has antioxidant properties. HDL contains the potent antioxidant enzyme paraoxonase, which may protect LDL lipids from oxidation. Thus, hypertriglyceridemia with... 

Whole plasma can also be fractionated into specific lipoprotein size classes to further resolve the underlying biochemistry and metabolism of tissues that deliver these lipids to blood and selectively remove them. Thus, TrueMass analysis can be used to measure the lipid profiles of very-low-density lipoprotein, quantify the lipid pathways responsible for metabolic changes in the liver and measure profiles of high-density lipoprotein to quantify the flux of lipids in reverse cholesterol transport. 

The HDL lipids are removed from the circulation by a selective uptake and by an indirect pathway. The selective uptake of cholesterol esters from HDL into he-patocytes and steroidogenic cells is mediated by the binding of HDL to scavenger receptor B1 (SR-BI). This selective uptake by SR-BI may depend on the presence of cofactors such as HL, which hydrolyses phospholipids on the surface of both HDL and plasma membranes and thereby enables the flux of cholesteryl esters from the lipoprotein core into the plasma membrane [42]. The indirect pathway involves the enzyme CETP, which exchanges cholesteryl esters of a-HDL with triglycerides of chylomicrons, VLDL, IDL, and LDL. The a-HDL derived cholesteryl esters are therefore removed via the LDL-receptor pathway. The removal of excess cholesterol from the periphery and the delivery to the liver for excretion in the bile is termed reverse cholesterol transport. 

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-... 

High-density (HDL) 50 1.063-1.210 Cholesterol transport (to liver for processing)... 

As mentioned in Chapter 21, there are several related receptors with similar structures. Two of them have a specificity for apolipoprotein E and can accept remnants of VLDL particles and chylomicrons.216 220 The LDL receptor-related protein is a longer-chain receptor.216 221 LDL particles, especially when present in excess or when they contain oxidized lipoproteins, may be taken up by endocytosis into macrophages with the aid of the quite different scavenger receptors.221 225 The uptake of oxidized lipoproteins by these receptors may be a major factor in promoting development of atherosclerosis (Box 22-B). On the other hand, scavenger receptor SR-B1, which is also present in liver cells, was recently identified as the receptor for HDL and essential to the "reverse cholesterol transport" that removes excess cholesterol for excretion in the bile.213/213a... 

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. 

Bile acids are sterol derivatives derived from cholesterol that have two major functions. (l) The cholesterol delivered back to the liver by reverse cholesterol transport is converted into bile acids, which are excreted from the body via the intestine. (2) The bile acids secreted into the intestine are required for the solubilization of dietary lipids so that they can be degraded by lipases and absorbed into the intestinal wall (see fig. 18.2). 

Glomset proposed the theory of reverse cholesterol transport in which HDL is involved in the return of cholesterol to the liver. 

The search for intestinal cholesterol transporters extended for many years, beginning with a debate about whether or not it was even a protein-facilitated process (4, 5). The pancreatic enzyme carboxyl ester lipase (CEL, also called cholesterol esterase) was believed to be important to this process (6,7) and several companies devoted considerable resources to the development and testing of compounds to inhibit CEL, with mixed results (8-10). These efforts were abandoned in the mid-1990s, however, after studies with gene-knockout mice demonstrated that the enzyme was important only for absorption of cholesteryl ester (11, 12), which is a minor component of dietary cholesterol and is present at very low levels in bile. Interestingly, CEL is also found in liver where it has been shown to affect HDL metabolism (13). Thus, it may ultimately play an important role in cholesterol metabolism and may yet prove to be a useful drug target for CVD treatment (Camarota and Howies, unpublished). 

Cholesterol can be obtained either from the diet or it can be synthesized de novo, mainly in the liver. Cholesterol is transported round the body in lipoprotein particles (see Topic K6). The rate of synthesis of cholesterol is dependent on the cellular level of cholesterol. High levels of cholesterol and its metabolites control cholesterol biosynthesis by ... 

VLDLs are synthesized in the liver and transport triacylglycerols, cholesterol and phospholipids to other tissues, where lipoprotein lipase hydrolyzes the triacylglycerols and releases the fatty acids for uptake. The VLDL remnants are transformed first to IDLs and then to LDLs as all of their apoproteins other than apoB-100 are removed and their cholesterol esterified. The LDLs bind to the LDL receptor protein on the surface of target cells and are internalized by receptor-mediated endocytosis. The cholesterol, which is released from the lipoproteins by the action of lysosomal lipases, is either incorporated into the cell membrane or re-esterified for storage. High levels of intracellular cholesterol decrease the synthesis of the LDL receptor, reducing the rate of uptake of cholesterol, and inhibit HMG CoA reductase, preventing the cellular synthesis of cholesterol. 

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