High-Density Lipoprotein: An Ambiguous Therapeutic Target in Atherosclerosis and Cardiovascular Disease

High-Density Lipoprotein: An Ambiguous Therapeutic Target in Atherosclerosis and Cardiovascular Disease A great majority of the morbidity and mortality worldwide can still be attributed to cardiovascular diseases, such as ischemic (coronary) heart disease, angina pectoris, and myocardial and cerebral infarction. Atherosclerosis, narrowing of the arteries because of arterial cholesterol deposition in macrophage foam cells, is the driving force behind the cardiovascular disease pathology. Water-soluble protein/lipid complexes called lipoproteins mediate the transport of cholesterol and other lipoid substances through the blood compartment. Relatively high levels of cholesterol associated with apolipoprotein B–containing low-density lipoprotein (LDL) particles predispose human subjects to the development of atherosclerosis and, thereby, increase the risk for cardiovascular disease. Apolipoprotein B–containing lipoproteins are, therefore, generally regarded as being proatherogenic factors. Cholesterol ester–rich high-density lipoprotein (HDL) particles use apolipoprotein A1 (apoA1) as their primary protein component. In sharp contrast to LDL, HDL is considered a potent anti-atherogenic agent. This notion is based on the fact that, in the general population, a strong inverse correlation exists between plasma levels of HDL cholesterol and the risk of cardiovascular disease. Of note, this inverse association seems to be independent of the level of cholesterol associated with proatherogenic LDL particles. As such, increasing plasma levels of HDL cholesterol has long been regarded a promising alternative therapy to supplement classical statin–based LDL cholesterol–lowering strategies that are able to reduce cardiovascular disease by only ≈30%. However, over the last decade, the enthusiasm for HDL as an interesting therapeutic target has been challenged by the HDL hypothesis critics because genetic association studies have excluded HDL cholesterol levels as determinants for cardiovascular disease risk. Furthermore, several therapeutic HDL-targeting approaches have proven insufficient to secure benefit for cardiovascular disease patients. Niacin is the most effective drug available in the clinic to raise plasma HDL cholesterol levels. Despite the fact that niacin is able to effectively raise plasma HDL cholesterol levels in patients who are treated with statins, the recent AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) testing the effect of niacin treatment on cardiovascular disease outcome in humans was stopped because of futility. Among patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of <70 mg/dL, addition of niacin to statin therapy did not reduce the composite risk of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization over a 36-month follow-up period. Cholesterol esters from HDL particles can be transferred to the apolipoprotein B–containing lipoproteins, very low– density lipoprotein, and LDL by cholesterol ester transfer protein (CETP) for subsequent removal from the blood circulation through whole particle uptake via the LDL receptor located on hepatocytes. In accordance with an important physiological role for CETP in HDL metabolism, drug-induced inhibition of CETP activity translates into a significant increase in plasma HDL cholesterol levels in humans. However, none of the recently developed CETP inhibitors tested in large-scale phase III clinical trials have, to date, been effective in lowering the risk for cardiovascular disease. Treatment with a combination of statins and dalcetrapib did not improve clinical outcome over treatment with statins alone. Addition of torcetrapib to statin therapy even increased the mortality rate in high-risk patients. Although the aforementioned clinical results at first indeed seem to argue against HDL as an anti-atherogenic factor, we actually consider these findings the strongest evidence for a crucial role of HDL in the protection against atherosclerosis and cardiovascular disease when taking into account data from studies in mice and humans that genetically lack a functional scavenger receptor BI (SR-BI). SR-BI is a HDL receptor that facilitates the removal of cholesterol esters from mature HDL species without parallel cellular whole particle uptake, a process also referred to as selective cholesterol ester uptake. High expression of SR-BI can be found in hepatocytes and adrenocortical cells that, respectively, use cholesterol for the synthesis of bile acids and steroid hormones, that is, glucocorticoids. Because hepatocytes of SR-BI knockout mice are unable to selectively take up cholesterol esters from human HDL, SR-BI is considered the sole mediator of selective HDL cholesterol uptake in the liver. HDL cholesterol ester clearance by the adrenal glands is also markedly diminished in SR-BI knockout mice. Total body SR-BI deficiency in mice and ablation of normal SR-BI protein functionality because of a P297S Functionality of High-Density Lipoprotein as Antiatherosclerotic Therapeutic Target