Impaired Cholesterol Metabolism and Enhanced Atherosclerosis in Clock Mutant Mice

Sep 10, 2013Circulation

Poor cholesterol processing and increased artery plaque in mice with disrupted body clocks

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Abstract

The dominant-negative Clock mutant protein (Clock(Δ19/Δ19) enhances plasma cholesterol and atherosclerosis in three different mouse models.

Clk(Δ19/Δ19)Apoe(-/-) mice exhibit hypercholesterolemia due to the accumulation of specific lipoproteins.
Increased intestinal cholesterol absorption contributes to elevated cholesterol levels in these mice.
High expression of key proteins involved in cholesterol transport is observed in the intestines of Clk(Δ19/Δ19)Apoe(-/-) mice.
Macrophages from Clk(Δ19/Δ19)Apoe(-/-) mice show increased uptake of modified lipoproteins and express higher levels of scavenger receptors.
These macrophages also exhibit low levels of a protein critical for cholesterol removal, indicating impaired cholesterol efflux.

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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 (Clock(Δ19/Δ19)) enhances plasma cholesterol and atherosclerosis in 3 different mouse models. Detailed analyses revealed that Clk(Δ19/Δ19)Apoe(-/-) 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 Clk(Δ19/Δ19)Apoe(-/-) mice was high and that enterocytes assembled and secreted more chylomicrons. Furthermore, we identified macrophage dysfunction as another potential cause of increased atherosclerosis in Clk(Δ19/Δ19)Apoe(-/-) mice. Macrophages from Clk(Δ19/Δ19)Apoe(-/-) mice expressed higher levels of scavenger receptors and took up more modified lipoproteins compared with Apoe(-/-) mice, but they expressed low levels of ATP binding casette protein family A member 1 and were defective in cholesterol efflux. Molecular studies revealed that Clock regulates ATP binding casette protein family A member 1 expression in macrophages by modulating upstream transcription factor 2 expression.

CONCLUSIONS: Clock(Δ19/Δ19) protein enhances atherosclerosis by increasing intestinal cholesterol absorption, augmenting uptake of modified lipoproteins by macrophages, and reducing cholesterol efflux from macrophages. These studies establish that circadian Clock activity is crucial in maintaining low plasma cholesterol levels and in reducing atherogenesis in mice.

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Impaired Cholesterol Metabolism and Enhanced Atherosclerosis in Clock Mutant Mice

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