Abstract 107: Impaired Lipid Metabolism and Enhanced Atherosclerosis in Clock Mutant Mice

Clock is a key transcription factor that controls circadian regulation. Here, we show that dominant-negative Clock mutant protein (Clock Δ19/Δ19 ) enhances hyperlipidemia and atherosclerosis in Apoe -/- mice. Clk [[Unable to Display Character: ∆]]19/[[Unable to Display Character: ∆]]19 Apoe -/- mice display hypercholesterolemia, show enhanced cholesterol absorption and express more NPC1L1, ACAT2 and MTP in the intestine. Macrophages from Clk [[Unable to Display Character: ∆]]19/[[Unable to Display Character: ∆]]19 Apoe -/- mice express high levels of scavenger receptors and take up more modified lipoproteins compared to Apoe -/- mice; but they express low levels of ABCA1 and are defective in cholesterol efflux. Molecular studies reveal that Clock regulates ABCA1 expression in macrophages by modulating USF2 expression. Thus, Clock Δ19/Δ19 protein enhances atherosclerosis by increasing intestinal cholesterol absorption by enterocytes, augmenting uptake of modified lipoproteins by macrophages and reducing cholesterol efflux from macrophages. These studies establish that circadian Clock plays a pivotal role in the regulation of cholesterol metabolism and atherosclerosis.