title: Why targeting HDL should work as a therapeutic tool, but has not.
abstract: Atherosclerosis is one of the most common causes of death and disability in the United States today despite the availability of statins, which reduce hyperlipidemia, a risk factor that predisposes individuals to this disease. Epidemiology of human populations has overwhelmingly demonstrated an inverse correlation between the concentration of plasma high-density lipoprotein (HDL) cholesterol (HDL-C) and the likelihood of developing cardiovascular disease (CVD). Decades of observations and mechanistic studies suggest that one protective function of HDL is its central role in reverse cholesterol transport. In this pathway, the ATP-binding cassette transporter A1 releases intracellular cholesterol, which is packaged with apolipoprotein A-I (apoA-I) into nascent HDL particles and released from the plasma membrane. Further lipidation and maturation of HDL occur in plasma with the eventual uptake by the liver where cholesterol is removed. It is generally accepted that CVD risk can be reduced if plasma HDL-C levels are elevated. Several different pharmacological approaches have been tried; the most popular approach targets the movement of cholesteryl ester from HDL to triglyceride-rich particles by cholesteryl ester transfer protein. Inhibition of cholesteryl ester transfer protein increases plasma HDL-C concentration; however, beneficial effects have yet to be demonstrated, likely the result of off-target effects. These revelations have led to a reevaluation of how elevating HDL concentration could decrease risk. A recent, landmark study showed that the inherent cholesterol efflux capacity of an individual's plasma was a better predictor of CVD status than overall HDL-C concentration. Even more provocative are recent studies showing that apoA-I, the principle protein component of HDL modulates cellular inflammation and oxidation. The following will review all these potential routes explaining how HDL apoA-I can reduce the risk of CVD.
authors.affiliation: Departments of *Pathology, Section of Lipid Sciences; and †Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sorci-Thomas
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thomas
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D004351:Drug Resistance; D006801:Humans; D052456:Hypoalphalipoproteinemias / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D057847:Lipid Regulating Agents / Q000627:therapeutic use*; D008075:Lipoproteins, HDL / Q000096:biosynthesis / Q000097:blood* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D058990:Molecular Targeted Therapy
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D057847:Lipid Regulating Agents; D008075:Lipoproteins, HDL; D002784:Cholesterol