Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis

High-density lipoproteins (HDL) possess key atheroprotective biological properties, including cellular cholesterol efflux capacity, and anti-oxidative and anti-inflammatory activities. Plasma HDL particles are highly heterogeneous in physicochemical properties, metabolism, and biological activity. Within the circulating HDL particle population, small, dense HDL particles display elevated cellular cholesterol efflux capacity, afford potent protection of atherogenic low-density lipoprotein against oxidative stress and attenuate inflammation. The antiatherogenic properties of HDL can, however be compromised in metabolic diseases associated with accelerated atherosclerosis. Indeed, metabolic syndrome and type 2 diabetes are characterized not only by elevated cardiovascular risk and by low HDL-cholesterol (HDL-C) levels but also by defective HDL function. Functional HDL deficiency is intimately associated with alterations in intravascular HDL metabolism and structure. Indeed, formation of HDL particles with attenuated antiatherogenic activity is mechanistically related to core lipid enrichment in triglycerides and cholesteryl ester depletion, altered apolipoprotein A-I (apoA-I) conformation, replacement of apoA-I by serum amyloid A, and covalent modification of HDL protein components by oxidation and glycation. Deficient HDL function and subnormal HDL-C levels may act synergistically to accelerate atherosclerosis in metabolic disease. Therapeutic normalization of attenuated antiatherogenic HDL function in terms of both particle number and quality of HDL particles is the target of innovative pharmacological approaches to HDL raising, including inhibition of cholesteryl ester transfer protein, enhanced lipidation of apoA-I with nicotinic acid and infusion of reconstituted HDL or apoA-I mimetics. A preferential increase in circulating concentrations of HDL particles possessing normalized antiatherogenic activity is therefore a promising therapeutic strategy for the treatment of common metabolic diseases featuring dyslipidemia, inflammation, and premature atherosclerosis.