Effects of probucol on cholesterol metabolism in mouse peritoneal macrophages: inhibition of HDL-mediated cholesterol efflux.
Macrophage-derived foam cells are known to play an essential role in the development and progression of atherosclerotic lesions. Probucol prevents oxidative modification of low-density lipoprotein (LDL) and lowers plasma contents of LDL and high-density lipoprotein (HDL). A recent report using apoE -/- mice demonstrated that probucol treatment enhanced atherosclerosis in apoE -/- mice more rapidly than that in untreated apoE -/- mice, and a reduction in plasma cholesterol by probucol was not the cause of enhancement of atherosclerotic lesions in probucol-treated apoE -/- mice. Moreover, probucol was reported to inhibit apoA-I mediated cholesterol efflux from mouse macrophages. These reports suggested that probucol might directly affect cholesterol metabolism in mouse macrophages. Thus, we investigated the effects of probucol on cholesterol metabolism in mouse resident peritoneal macrophages. Probucol did not affect degradation of acetylated LDL (Ac-LDL), degradation of LDL and endogenous cholesterol synthesis in mouse macrophages. However, it significantly inhibited HDL-mediated cholesterol efflux. Moreover, probucol partially (30%) inhibited the binding of HDL to mouse macrophages, and significantly activated acyl-coenzyme A:cholesterol acyltransferase (ACAT). Our results suggested that probucol inhibited HDL-mediated cholesterol efflux by inhibiting the binding of HDL to mouse macrophages and reducing HDL-accessible free cholesterol content by ACAT activation, thereby worsening atherosclerotic lesions in apoE -/- mice. However, it remains unclear whether probucol inhibits HDL-mediated cholesterol efflux from human macrophages.
Takemura
T
T
Department of Metabolic Medicine, Kumamoto University School of Medicine, Honjo 1-1-1, 860-8556, Kumamoto, Japan.
Sakai
M
M
Matsuda
H
H
Matsumura
T
T
Biwa
T
T
Anami
Y
Y
Nishikawa
T
T
Sasahara
T
T
Shichiri
M
M
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice; D011341:Probucol / Q000494:pharmacology*; D002785:Sterol O-Acyltransferase / Q000378:metabolism
D000924:Anticholesteremic Agents; D008076:Cholesterol, HDL; D002784:Cholesterol; D002785:Sterol O-Acyltransferase; D011341:Probucol