HDL quality and functionality: what can proteins and genes predict?

Abstract

Epidemiological and clinical studies have over the years established that dyslipidemia constitutes the main risk factor for atherosclerosis. The inverse correlation between HDL cholesterol (HDL-C) levels and coronary heart disease morbidity and mortality identified HDL-C as an alternative pharmacological target to LDL-C and a potential anti-atherosclerosis marker. However, more recent data reinforced the principle of ‘HDL quality’ in atherosclerosis that refers to the functionality of HDL particle, as defined by its protein and lipid content, rather than HDL-C levels in plasma. Since HDL functionality depends on the genes and proteins of the HDL metabolic pathway, its apoprotein composition may serve as a surrogate marker of atheroprotection. In this manuscript we review the atheroprotective properties of HDL in relation to the proteins of HDL metabolic pathway and discuss what HDL-associated genes and proteins may reveal about HDL functionality in the assessment of coronary risk.

Keywords::

• apolipoproteins
• function
• HDL
• HDL modifying enzymes
• structure

Financial & competing interests disclosure

The authors were supported by the action “Excellence” of the Operational Program “Education and Lifelong Learning” (Action’s Beneficiary: General Secretariat for Research and Technology) and is cofinanced by the European Social Fund and the Greek State. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• HDL is a lipoprotein and not just a cholesterol. The particles of HDL are composed of apolipoproteins, phospholipids, free and esterified cholesterol, triglycerides and enzymes. Also, HDL particles are distributed in various subpopulations depending on their composition, geometry and size.

• HDL particles possess a number of antiatherogenic properties. In addition to HDL-cholesterol (HDL-C) levels, the functions of HDL are important determinants of HDL-mediated atheroprotection.

• To this date, raising HDL-C by pharmacological means had no significant effects on coronary risk.

• HDL is synthesized in the circulation by apolipoprotein A-I and other apolipoproteins in a pathway that involves ATP-binding cassette transporter A1, ATP-binding cassette transporter G1 and lecithin: cholesterol acyl transferase. Other HDL-modifying enzymes, such as hepatic lipase, endothelial lipase and cholesteryl ester transfer protein, are important modulators of the functions of plasma HDL.

• The apolipoproteins of HDL are important modulators of the activity of enzymes of the HDL metabolic pathway, which in turn affect HDL properties. Thus, the relative apolipoprotein composition of HDL may serve as a surrogate marker of HDL-mediated atheroprotection.

• Genetic mutations that result in increased plasma HDL-C levels do not seem to lower risk of myocardial infarction. Interventions that raise plasma HDL-C cannot be assumed to lead to a corresponding benefit with respect to the risk of myocardial infarction.

• Genome-wide association studies that correlate haplotypes with HDL functions may identify in the future invaluable markers for the atheroprotective potential of HDL.

Notes