Metabolism of HDL

Absorption, Distribution, Metabolism, and Excretion. There is an obvious data need to determine the pharmacokinetic and toxicokinetic behavior of HDl in both humans and laboratory animals. Determination of blood levels of inhaled, ingested and dermally absorbed HDl would be difficult, given the very short half-life in biological matrices (Berode et al. 1991) and the rate at which HDl binds to proteins in the blood. Although some information is known about the metabolism of HDl in humans inhaling a known quantity of HDl (Brorson et al. 1990), the rate at which absorption occurs, where the majority of the metabolism of HDl occurs (in the water in the mucous layer of the bronchi as opposed to the blood or the kidney), and the distribution patterns and toxic effects of the metabolite (if any) are not well described. Information in these areas of toxicokinetics and toxicodynamics could also be useful in developing a PBPK/PD model for HDl. Research should focus on the respiratory and dermal routes of exposure. 

Metabolism of HDL. PC = phosphatidylcholine lyso-PC = lysophosphatidylcholine. PC AT = Phosphatidylcholine cholesterol transferase. 

The metabolism of HDL probably involves interaction with both hepatic and peripheral cells, as well as with other lipoproteins. HDL may remove cholesterol from tissues, the "scavenger hypothesis (11,12). The cholesterol may then be esterifed by the action of lecithin cholesterol acyl transferase. HDL may provide cholesterol to the liver for bile acid synthesis (13) and some HDL may be catabolized by the liver in the process. HDL has not been found to interfere with the binding of LDL in cultured human fibroblasts (6). However, in cultured human arterial cells, porcine or rat hepatocytes, and rat adrenal gland, there appears to be some competition of HDL with LDL binding sites, suggesting the presence of a "lipoprotein-binding" site (14). 

The metabolism of HDL is less well defined than that of the other lipoprotein classes. Reasons for this include the heterogeneous nature of HDL and the interchange of both lipid and protein components between HDL and other lipoproteins. Furthermore, HDL are not removed from the circulation, because whole particles and their different components have different metabolic fates. 

Lecithin-cholesterol acyltransferase is a water-soluble plasma enzyme that plays an important role in the metabolism of HDLs by catalyzing the formation of cholesteryl esters on HDLs through the transfer of fatty acids from the sn-2 position of phosphatidylcholine to cholesterol (Jonas, 1986). ApoA-1 is the major cofactor of LCAT in HDLs and reconstituted lipoproteins (Fielding et ai, 1972). Many laboratories have used techniques such as synthetic peptide analogs (Anantharamaiah et ai, 1990a Anantharamaiah, 1986), monoclonal antibodies (Banka et al., 1990), and recombinant HDL particles (Jonas and Kranovich, 1978) to attempt to identify the major LCAT-activating region of apoA-I. 

Stein, Y., et al. 1983. Metabolism of HDL-cholesteryl ester in the rat, studied with a nonhydrolyzable analog, cholesteryl linoleyl ether. Biochim. Biophys. Acta 752 98-105. 

The metabolism of HDL involves several different enzymes and transfer proteins but is not completely understood [7]. The major apolipoprotein of HDL is apoA-I. The liver and intestine are the sources of apoA-I, which interacts with peripheral cells to remove excess cellular cholesterol via the ATP-binding cassette protein A1 (ABCAl). Unesterified cholesterol associated with nascent HDL is a substrate for the plasma enzyme lecithin cholesterol acyltransferase (LCAT), resulting in the formation of cholesteryl ester and enlargement of the HDL particle. Genetic defects in apoA-I, ABCAl and LCAT can cause low levels of HDL, termed hypoalphalipopro-teinemia. HDL cholesteryl ester is transferred to apoB-containing lipoproteins (such as LDL) by the cholesteryl ester transfer protein (CETP) and can be returned to the liver via the LDL receptor. HDL may also deliver some cholesterol directly to the liver via the scavenger receptor class BI (SR-BI). The removal of excess cholesterol from peripheral cells and delivery to the liver for excretion in the bile is a process that has been termed reverse cholesterol transport . 

PLTP is responsible for the majority of phospholipid transfer activity in human plasma. Specifically, it transfers surface phospholipids from VLDL to HDL upon lipolysis of triglycerides present in VLDL. The exact mechanism by which PLTP exerts its activity is yet unknown. The best indications for an important role in lipid metabolism have been gained from knockout experiments in mice, which show severe reduction of plasma levels of HDL-C and apoA-I. This is most likely the result of increased catabolism of HDL particles that are small in size as a result of phospholipid depletion. In addition to the maintenance of normal plasma HDL-C and apoA-I concentration, PLTP is also involved in a process called HDL conversion. Shortly summarized, this cascade of processes leads to fusion of HDL... 

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... 

Disorders of lipoprotein metabolism involve perturbations which cause elevation of triglycerides and/or cholesterol, reduction of HDL-C, or alteration of properties of lipoproteins, such as their size or composition. These perturbations can be genetic (primary) or occur as a result of other diseases, conditions, or drugs (secondary). Some of the most important secondary disorders include hypothyroidism, diabetes mellitus, renal disease, and alcohol use. Hypothyroidism causes elevated LDL-C levels due primarily to downregulation of the LDL receptor. Insulin-resistance and type 2 diabetes mellitus result in impaired capacity to catabolize chylomicrons and VLDL, as well as excess hepatic triglyceride and VLDL production. Chronic kidney disease, including but not limited to end-stage... 

Genetic disorders of HDL metabolism have also resulted in greater understanding of the molecular regulation of HDL metabolism. Nonsense or missense mutations in apoA-I can result in substantially reduced HDL-C levels due to rapid catabolism of structurally abnormal or truncated apoA-I proteins. Tangier disease is a rare autosomal codominant disorder characterized by markedly low HDL-C and apoA-I levels and caused... 

Rader DJ (2006) Molecular regulation of HDL metabolism and function implications for novel therapies. J Clin Invest 116 3090-3100... 

Figure 25-5. Metabolism of high-density lipoprotein (HDL) in reverse cholesteroi transport. (LCAT, lecithinxholesterol acyltransferase C, cholesterol CE, cholesteryl ester PL, phospholipid A-l, apolipoprotein A-l SR-Bl, scavenger receptor B1 ABC-1, ATP binding cassette transporter 1.) Prep-HDL, HDLj, HDL3—see Table 25-1. Surplus surface constituents from the action of lipoprotein lipase on chylomicrons and VLDL are another source of preP-HDL. Hepatic lipase activity is increased by androgens and decreased by estrogens, which may account for higher concentrations of plasma HDLj in women.

Lipoproteins. A lipoprotein is an endogenous macromolecule consisting of an inner apolar core of cholesteryl esters and triglycerides surrounded by a monolayer of phospholipid embedded with cholesterol and apoproteins. The functions of lipoproteins are to transport lipids and to mediate lipid metabolism. There are four main types of lipoproteins (classified based on their flotation rates in salt solutions) chylomicrons, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL). These differ in size, molecular weight, and density and have different lipid, protein, and apoprotein compositions (Table 11). The apoproteins are important determinants in the metabolism of lipoproteins—they serve as ligands for lipoprotein receptors and as mediators in lipoproteins interconversion by enzymes. 

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 metabolism of VLDL is very similar to that of chylomicrons, the major difference being that VLDL are assembled in hepatocytes to transport triglyceride containing fatty acids newly synthesized from excess glucose, or retrieved from the chylomicron remnants, to adipose tissue and musde. ApoB-100 is added in the hepatocytes to mediate release into the blood. Like chylomicrons, VLDL acquire apoC-II and apoE from HDL in the blood, and are metabolized by lipoprotein lipase in adipose tissue and musde. 

The best-known effect of APOE is the regulation of lipid metabolism (see Fig. 10.13). APOE is a constituent of TG-rich chylomicrons, VLDL particles and their remnants, and a subclass of HDL. In addition to its role in the transport of cholesterol and the metabolism of lipoprotein particles, APOE can be involved in many other physiological and pathological processes, including immunoregu-lation, nerve regeneration, activation of lipolytic enzymes (hepatic lipase, lipoprotein lipase, lecithin cholesterol acyltransferase), ligand for several cell receptors, neuronal homeostasis, and tissue repair (488,490). APOE is essential... 

However, very low plasma levels of HDL cholesterol are also found in patients with genetically disturbed metabolic pathways that are indirectly linked to HDL metabolism. For example, many patients with lipid storage diseases like Gaucher s disease (glucocerobrosidase deficiency, OMIM 230800-231000), Nieman-Pick disease types A or (sphingomyelinase deficiency, OMIM 257200 and 607616, respectively), Niemann-Pick disease type C (OMIM 257220), hypertriglyceridemia, or diabetes mellitus present with low HDL cholesterol [22]. 

Although of much less clinical relevance, it must be emphasized that certain disturbances of HDL metabolism cause familial aggregation of elevated HDL cholesterol... 

Hovingh GK, de Groot E, van der Steeg W, Boekholdt SM, Hutten BA, Kuivenhoven JA, Kastelein JJ (2005) Inherited disorders of HDL metabolism and atherosclerosis. Curr Opin Lipidol 16 139-145... 

Although elevated levels of cholesterol and LDL in human plasma are linked to an increased incidence of cardiovascular disease, recent data have shown that an increase in concentration of HDL in plasma is correlated with a lowered risk of coronary artery disease. Why does an elevated HDL level in plasma appear to protect against cardiovascular disease, whereas an elevated LDL level seems to cause this disease The answer to this question is not known. An explanation currently favored is that HDL functions in the removal of cholesterol from nonhepatic tissues and the return of cholesterol to the liver, where it is metabolized and secreted. The net effect would be a decrease in the amount of plasma cholesterol available for deposit in arteries (see... 

The metabolism of cholesterol in mammals is extremely complex. A summary sketch (fig. 20.24) helps to draw the major metabolic interrelationships together. Cholesterol is biosynthesized from acetate largely in the liver (fig. 20.24a) or taken in through the diet (fig. 20.24b). From the intestine, dietary cholesterol is secreted into the plasma mainly as a component of chylomicrons. The triacylglycerol components of chylomicrons are quickly degraded by lipoprotein lipase, and the remnant particles are removed by the liver. Apoproteins and lipid components of the chylomicrons and remnants appear to exchange with HDL. Cholesterol made in the liver (fig. 20.24a) has several alternative fates. It can be (1) secreted into plasma as a component of VLDL,... 

A PK/PD relationship in humans has recently been reported for a novel hypolipidemic agent, ISIS 301012, a 2 -MOE partially modified antisense inhibitor of human apoB-100 [59, 64]. ApoB-100 is a structural component of LDL-cholesterol, and plays a key role in its metabolism and transport Prefiminary data from this study indicate that antisense inhibition of apoB-100 results in both dose- and concentration-dependent sustained reductions in serum levels of apoB-100, LDL-cho-lesterol and total cholesterol, but does not affect levels of HDL-cholesterol. 

It is, of course, also possible that the esterified cholesterol formed in HDL may be removed from plasma by some process other than uptake of the whole HDL particle or LTP-I-mediated transfer to other lipoprotein particles, but this possibility has not been fully investigated. Some evidence that there may be other pathways than these for the removal from plasma of HDL esterified cholesterol comes from the studies of Class et al. (G5, G6), who showed that cholesteryl ether incorporated in rat HDL as a tracer for cholesteryl ester was taken up in vivo by the rat liver (and by other organs) fester than apoA-I tracer (see Section 4.1.2). These studies are complicated by the relatively high concentration of apoE in rat HDL (compared, for instance, to man) and the unknown effect of apoE on HDL cholesteryl ester metabolism in the rat. Further studies on the removal of esterified cholester-... 

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