Of Mice and Men

Abstract

IAn increasing body of evidence suggests that disturbed HDL metabolism increases the risk of cardiovascular disease (CVD).1 HDL metabolism is central to reverse cholesterol transport (RCT), in which excess cholesterol from peripheral tissue is returned to the liver for extracorporeal elimination. HDLs also have non-RCT functions including antiinflammatory, antioxidant, and antithrombotic properties. These may relate collectively to the apoA-I content of HDL particles. A number of therapeutic approaches that target HDL metabolism may be useful in preventing and regressing atherosclerosis and coronary disease.2–3 See accompanying article on page 2016 Among lipid-regulators, niacin (nicotinic acid, vitamin B3, pyridine-3-carboxylic acid) is the most effective therapeutic agent presently available for elevating HDL-cholesterol and apoA-I. Notwithstanding issues with tolerability, niacin has long been available for treating atherogenic dyslipidemias. Data from several clinical trials collectively demonstrate that niacin alone or in combination with other agents, including statins, can reduce cardiovascular events and progression of coronary atherosclerosis.4 The precise therapeutic mechanism(s) of action of niacin remains unclear, but may largely involve a favorable regulation of HDL metabolism. But exactly how it mediates this effect has not yet been elucidated. In this issue of Atherosclerosis, Thrombosis and Vascular Biology , van der Hoorn et al present data in a new animal model on the mechanism of the effect of niacin on HDL metabolism.5 First, they demonstrated that niacin increased plasma HDL-cholesterol concentration in the APOE * 3Leiden.CETP ( E3L.CETP ) mouse model (ie, E3L mice crossbred with human CETP-expressing mice) but not in the E3L model alone. Second, in a matched study design they showed in E3L.CETP mice on a Western-type diet that niacin (118 mg/kg/d, 360 mg/kg/d and 1180 mg/kg/d for at least 3 weeks) dose-dependently increased plasma HDL-cholesterol and apoA-I concentrations by several mechanisms involving reductions in plasma VLDL-triglyceride concentrations and in the …