HDL STRUCTURE AND ATHEROPROTECTIVE FUNCTIONS IN INHERITED HDL DISORDERS

The plasma concentration of cholesterol in high density lipoproteins (HDL-C) is inversely correlated with the incidence of coronary heart disease (CHD), thus leading to the general definition of HDL-C as “good cholesterol”. The protective effect of HDL against CHD is mainly due to their role in promoting the transport of cholesterol from peripheral tissues, including the arterial wall, to the liver for the excretion and to their ability to preserve the homeostasis of the vascular endothelium. Rare mutations in different genes can cause inherited HDL disorders, characterized by a dramatic reduction (familial hypoalphalipoproteinemia, FHALP) or increase (familial hyperalphalipoproteinemia, FHrALP) of HDL-C levels. Among the known causes of FHALP are mutations in the apoA-I, ABCA1 and LCAT genes; the best known monogenic cause of FHrALP is a mutation in the CETP gene abolishing CETP activity. Theoretically, FHALP cases should have an increased risk of CHD, while FHrALP subjects should be protected from premature CHD; however, there are paradoxical exceptions to this rule. A new concept is now emerging, that is looking not only at HDL-C level, but also at HDL function. Thus, the project proposed to Telethon by our group is aimed at evaluating the ability of HDL from FHALP and FHrALP cases to exert some of their known protective activities. These data will improve the identification of carriers of inherited HDL disorders in which HDL are functionally altered and that can be really exposed to an increased CHD risk. In addition, the results can help the identification of novel therapeutic strategies aimed at normalizing HDL functionality in carriers of inherited HDL disorders.