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Abstract
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.
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.
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.
[1
]From the Division of Molecular Medicine, the Department of Medicine (L.Y.-C., J.K.,
T.P., H.L., and A.R.T.), Columbia University, New York, NY; and Merck (B.H., T.F.,
C.P.S., and A.K.T.), Rahway, NJ.