HDL and the progression of atherosclerosis: new insights

Aims Lowering low-density lipoprotein (LDL) cholesterol or raising high-density lipoprotein (HDL) cholesterol can result in significant cardiovascular benefit, both in terms of reduction of events and also, to a variable extent, of atheromatous lesions. LDL and HDL have opposite roles in body cholesterol regulation and, both reduced deposition (LDL reduction) and increased removal (raised HDL) can improve vascular disease. Very recently, studies using recombinant apolipoprotein Al liposomes (in particular with the mutant apo Al-Milano) have shown that direct infusion can effectively remove cellular cholesterol and dramatically reduce established atheromatous plaques in animals and in coronary patients. It has thus become of growing interest, the possibility of raising HDL by pharmacological treatments. This review will attempt to investigate existing and novel methodologies for HDL raising. Methods and results HDL raising can be achieved by using drugs active on the peroxisome proliferator activated receptor alpha (PPAR alpha) system, particularly using fibrates or n-3 fatty acids and, possibly more effectively, by using nicotinic acid. The activity of this agent has been traditionally linked to a reduced free fatty acid (FFA) mobilization from adipose tissue. More recently, it has been noted that nicotinic acid can activate the PPAR system, by stimulating all three PPAR isoforms (alpha, gamma, delta). This mode of action seems to more effectively explain the striking HDL-raising properties of the drug. Conclusions Newly discovered mechanisms of nicotinic acid can explain, on the one hand, reduced atherosclerosis progression in secondary prevention patients treated with statins and, on the other hand, improved body cholesterol mobilization, effectively reducing cholesterol pool sizes.