Impaired Cholesterol Metabolism and Enhanced Atherosclerosis in Clock Mutant Mice

Abstract

Background—Clock is a key transcription factor that positively controls circadian regulation. However, its role in plasma cholesterol homeostasis and atherosclerosis has not been studied. Methods and Results—We show for the first time that dominant-negative Clock mutant protein (ClockΔ19/Δ19) enhances plasma cholesterol and atherosclerosis in 3 different mouse models. Detailed analyses revealed that ClkΔ19/Δ19Apoe−/− mice display hypercholesterolemia resulting from the accumulation of apolipoprotein B48–containing cholesteryl ester–rich lipoproteins. Physiological studies showed that enhanced cholesterol absorption by the intestine contributes to hypercholesterolemia. Molecular studies indicated that the expression of Niemann Pick C1 Like 1, Acyl-CoA:Cholesterol acyltransferase 1, and microsomal triglyceride transfer protein in the intestines of ClkΔ19/Δ19Apoe−/− mice was high and that enterocytes assembled and secreted more chylomicrons. Furthermore, we identified macrophage dysfunction as another potent...