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La funzione delle HDL dopo acido nicotinico e anacetrapib

Il primo inibitore della proteina di trasporto lipidico (CETP), il torcetrapib, ha mantenuto le promesse di produrre un forte aumento delle HDL, ma ha fallito sul piano clinico forse per effetti collaterali, ma forse anche perché le HDL così prodotte erano disfunzionali. In questo studio si è voluto saggiare la capacità delle HDL di soggetti trattati con anacetrapib, un nuovo inibitore del CETP, di promuovere l'efflusso di colesterolo da macrofagi. Il livello di colesterolo HDL è aumentato del 100% nei soggetti trattati con anacetrapib e del 30% in quelli trattati con acido nicotinico che fungevano da gruppo di confronto. Le HDL di soggetti trattati con anacetrapib hanno mostrato una maggiore capacità di rimozione del colesterolo dai macrofagi ed anche una maggiore azione antiinfiammatoria.

Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib

Yvan-Charvet L, Kling J, Pagler T, Li H, Hubbard B, Fisher T, Sparrow CP, Taggart AK, Tall AR.

Arterioscler Thromb Vasc Biol 2010;30:1430-38

OBJECTIVE: To examine the effects of treatments with niacin or anacetrapib (an inhibitor of cholesteryl ester transfer protein) on the ability of high-density lipoprotein (HDL) to promote net cholesterol efflux and reduce toll-like receptor-mediated inflammation in macrophages.
METHODS AND RESULTS: A total of 18 patients received niacin, 2 g/d, for 4 weeks; 20 patients received anacetrapib, 300 mg/d, for 8 weeks; and 2 groups (n=4 and n=5 patients) received placebo. HDL samples were isolated by polyethylene glycol precipitation or ultracentrifugation, tested for the ability to promote cholesterol efflux in cholesterol-loaded THP-I or mouse peritoneal macrophages, or used to pretreat macrophages, followed by lipopolysaccharide exposure. HDL cholesterol levels were increased by 30% in response to niacin and by approximately 100% in response to anacetrapib. Niacin treatment increased HDL-mediated net cholesterol efflux from foam cells, primarily by increasing HDL concentration, whereas anacetrapib treatment increased cholesterol efflux by both increasing HDL concentration and causing increased efflux at matched HDL concentrations. The increased efflux potential of anacetrapib-HDL was more prominent at higher HDL cholesterol concentrations (>12 microg/mL), which was associated with an increased content of lecithin-cholesterol acyltransferase (LCAT) and apolipoprotein E and completely dependent on the expression of ATP binding cassette transporters (ABCA1 and ABCG1). Potent antiinflammatory effects of HDL were observed at low HDL concentrations (3 to 20 microg/mL) and were partly dependent on the expression of ABCA1 and ABCG1. All HDL preparations showed similar antiinflammatory effects, proportionate to the HDL cholesterol concentration.
CONCLUSIONS: Niacin treatment caused a moderate increase in the ability of HDL to promote net cholesterol efflux, whereas inhibition of cholesteryl ester transfer protein via anacetrapib led to a more dramatic increase in association with enhanced particle functionality at higher HDL concentrations. All HDLs exhibited potent ability to suppress macrophage toll-like receptor 4-mediated inflammatory responses, in a process partly dependent on cholesterol efflux via ABCA1 and ABCG1.

Arterioscler Thromb Vasc Biol 2010;30:1430-38