title: 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.
  
  
  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.
authors.affiliation: Departments of Cell Biology and Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY.
authors.forename: Xiaoyue
authors.initials: X
authors.lastname: Pan
authors.forename: Xian-Cheng
authors.initials: XC
authors.lastname: Jiang
authors.forename: M Mahmood
authors.initials: MM
authors.lastname: Hussain
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D018955:CD36 Antigens / Q000378:metabolism; D056926:CLOCK Proteins / Q000235:genetics* / Q000378:metabolism; D002784:Cholesterol / Q000097:blood*; D002940:Circadian Rhythm / Q000235:genetics*; D016207:Cytokines / Q000097:blood; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D006706:Homeostasis / Q000235:genetics; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism; D007408:Intestinal Absorption / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051720:Upstream Stimulatory Factors / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D001057:Apolipoproteins E; D018955:CD36 Antigens; D056926:CLOCK Proteins; D002784:Cholesterol; D016207:Cytokines; D051720:Upstream Stimulatory Factors; C577833:Abca1 protein, mouse; C497186:Usf2 protein, mouse; C538944:Clock protein, mouse
keywords: ATP binding cassette transporter 1; CLOCK proteins; atherosclerosis; cholesterol; circadian rhythm; lipid metabolism; upstream transcription factor 2