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Abstract

Abstract 

  1. Plasma high-density lipoproteins (HDL) consist of about 50 percent protein and 50 percent lipids. The principal apolipoproteins of HDL, apo A-I and apo A-II, are synthesized in the liver (apo A-I and apo A-II) or small intestine (apo A-I), secreted as components of triglyceride (TG)-rich lipoproteins (TRL), and then transferred into HDL during lipolysis, along with phospholipid and cholesterol. Alternatively, they may be secreted as free apoproteins, then acquire lipids by interaction with the cellular ATP binding cassette transporter, ABC1. The plasma cholesterol-esterifying enzyme lecithin: cholesterol acyltransferase (LCAT) circulates bound to HDL and uses free cholesterol and phospholipids as substrates in the generation of cholesteryl esters (CE). HDL also contains a phospholipid transfer protein (PLTP) and a cholesteryl ester transfer protein (CETP), which mediate the transfer of phospholipid and cholesterol into HDL and the removal of cholesteryl esters from HDL, respectively. CETP mediates a hetero-exchange of HDL CE for TG of TRL, and the HDL TG is subsequently hydrolyzed by hepatic lipase (HL). The coordinate activities of PLTP, CETP, LCAT, and HL promote the formation and turnover of HDL CE, which is a central event in the transport of cholesterol from peripheral tissues to the liver, that is, reverse cholesterol transport. The return of plasma HDL CE to the liver may involve transfer to TRL by CETP, selective uptake of free and esterified cholesterol (i.e., cellular uptake of HDL lipid without protein degradation), or uptake of holo-HDL particles. An authentic HDL receptor, scavenger receptor BI (SR-BI), is highly expressed in the liver and steroidogenic tissues, where it mediates the selective uptake of HDL lipids.

  2. Plasma HDL levels show an inverse relationship to atherosclerotic cardiovascular disease. Underlying this relationship is the ability of HDL to promote the efflux of cholesterol from foam cells in the arterial wall and to mediate reverse cholesterol transport. Transgenic mouse studies strongly support an antiatherogenic role of HDL, and are consistent with increased reverse cholesterol transport as the underlying mechanism. Antiatherogenic properties of HDL may also be related to its ability to inhibit the retention, aggregation, and oxidation of LDL in the arterial wall. Humans with low HDL often have increased levels of TRL; in some cases, low HDL is likely a marker for a metabolic predisposition to accumulate atherogenic remnants of TRL. Subjects with low HDL typically have increased catabolism of apo A-I, a process that may be driven by increased core lipid exchange between HDL and TRL. In other cases low HDL may be a marker of an inflammatory state involving the vessel wall.

  3. Transgenic mouse models have proven invaluable in elucidating the metabolism of HDL and its relationships to atherosclerosis. Human apo A-I transgenic mice show increased HDL cholesterol and have human-like subspecies of HDL in plasma. Importantly, apo A-I transgenic mice are resistant to the development of early atherosclerotic lesions in response to an atherogenic diet. Moreover, the apo A-I transgene inhibits the development of both early and late complex atherosclerotic lesions in apo E knockout (KO) mice. These experiments provide compelling evidence for a direct antiatherogenic function of HDL. Similar results have been reported when another HDL apolipoprotein, apo A-IV, is overexpressed in mice. However, human apo A-II transgenic mice do not have increased HDL cholesterol levels, and are not protected from atherosclerosis. Gene knockout of apo A-I results in decreased HDL cholesterol levels but does not increase atherosclerosis susceptibility in response to diet or the apo E KO background; apo A-I KO mice show a modest increase in atherosclerosis susceptibility in the presence of an atherogenic stimulus provided by the apo B transgene. These results suggest that multiple genes (apo A-I, apo A-IV) with redundant functions mediate antiatherogenic properties of HDL in response to specific atherogenic stimuli.

  4. Genetic manipulation of the HDL processing factors (enzymes, lipid transfer proteins, and receptors) has also provided insight into their role in HDL metabolism. Mice or rabbits transgenic for LCAT show increased HDL cholesterol levels, and LCAT transgenic rabbits are protected from atherosclerosis. CETP transgenic mice have decreased HDL cholesterol and apo A-I levels, increased clearance of HDL CE in the liver, and variable atherosclerosis depending on the metabolic context. Crossbreeding of CETP transgenic mice with hypertriglyceridemic apo C-III transgenic mice results in a synergistic lowering of HDL cholesterol and decrease in HDL size and illustrates how hypertriglyceridemia causes decreased HDL cholesterol levels in the presence of CETP. Gene KO of PLTP results in decreased HDL cholesterol and apo A-I levels, reflecting diminished transfer of phospholipids from TRL into HDL. Mice and rabbits transgenic for HL show reduced HDL cholesterol and apo A-I levels; conversely, HL KO mice have increased levels of HDL. HL KO/apo E KO mice have decreased atherosclerosis compared to apo E KO mice, perhaps due to higher HDL levels. Recent transgenic studies have shown a major role for SR-BI in HDL metabolism, in the selective uptake of HDL lipids in the liver and steroidogenic tissues, and a protective effect of SR-BI on atherosclerosis.

  5. Reduced HDL cholesterol levels (hypoalphalipoproteinemia) are often familial, may be accompanied by increased triglyceride levels, and are associated with increased CHD risk. In most instances, the genetic basis is unknown. Occasionally, hypoalphalipoproteinemia results from mutations in the apo A-I/apo C-III/apo A-IV gene complex, or from the rare recessive disorders, LCAT deficiency or Tangier disease (see Chaps. 118 and 122). Tangier disease is caused by homozygous mutations in ABC1 and heterozygous mutations may cause familial hypoalphalipoproteinemia. In some families, a gene inversion of apo A-I/apo C-III/apo A-IV has resulted in deletion of the whole cluster and leads to profoundly decreased HDL levels and premature atherosclerosis. Approximately 13 different functionally significant isolated mutations of the apo A-I gene have been described. These result in markedly decreased HDL cholesterol and apo A-I levels and are often associated with corneal opacities and a predisposition to premature coronary heart disease. However, the latter is not uniform and subjects are frequently healthy. A missense mutation of apo A-I (apo A-I Milano) is associated with reduced HDL and LDL cholesterol and has been anecdotally associated with a reduced predisposition to CHD. As in transgenic mouse studies, it appears that the levels of atherogenic lipoproteins may be important contributing factors to the impact of hypoalphalipoproteinemia on CHD in humans; that is, low HDL only appears to be a risk factor in the context of an accompanying atherogenic stimulus. Apo A-II deficiency is extremely rare and does not appear to be associated with altered HDL cholesterol or CHD susceptibility.

  6. Increased HDL levels (hyperalphalipoproteinemia) commonly have a genetic basis. In the Japanese, heterozygous mutations in the CETP gene are present in 5 to 7 percent of the general population and represent a common cause of increased HDL levels. Homozygous deficiency of CETP results in massive elevations of HDL cholesterol and apo A-I and the accumulation of large CE- and apo E-rich HDL species. Heterozygous deficiency of CETP results in milder (10 to 30 percent) increases in HDL cholesterol. An evaluation of the relationship of CETP mutations to coronary heart disease in Japanese-American men of the Honolulu Heart Program cohort indicates an overall increase in risk of coronary heart disease in subjects with the mutations, consistent with the idea that the protective role of HDL may be related to reverse cholesterol transport. However, the relationship of CETP mutations to CHD appears complex, as subjects with CETP mutations and HDL cholesterol >60 mg/dl enjoy a low prevalence of CHD. Rare null or missense mutations in the HL gene are also a cause of increased HDL levels. Subjects with these mutations have increased HDL cholesterol, apo A-I, and triglyceride levels. They accumulate large, buoyant LDL species, representing VLDL remnants. Although some subjects with HL deficiency accumulate beta-VLDL and have premature CHD, this may reflect concomitant genetic defects in these families.

  7. Twin and family studies suggest that about 50 percent of the variance of HDL cholesterol levels in the general population is attributable to genetic factors. In the Japanese, about 10 percent of the variance in HDL cholesterol levels is attributable to CETP gene mutations (see above). Recently, sib-pair linkage analysis has demonstrated that common variations at the HL and apo A-I/apo C-III/apo A-IV gene loci are responsible for the major portion of the genetic component of the variance in HDL cholesterol in healthy, normolipidemic Caucasians. These genetic variants are not associated with coding sequence changes and may represent common promoter mutations. A haplotype of the HL gene that is associated with increased HDL cholesterol levels has been defined. Moreover, this haplotype of HL is common in African-Americans and in part explains their higher HDL cholesterol levels.

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