CREM modulates the circadian expression of CYP51, HMGCR and cholesterogenesis in the liver.
We show for the first time that isoforms of the cAMP response element modulator Crem, regulate the circadian expression of Cyp51 and other cholesterogenic genes in the mouse liver. In the wild type mice the expression of Cyp51, Hmgs, Fpps, and Sqs is minimal between CT12 and CT16 and peaks between CT20 and CT24. Cyp51, Fpps, and Sqs lost the circadian behavior in Crem-/- livers while Hmgcr is phase advanced from CT20 to CT12. This coincides with a phase advance of lathosterol/cholesterol ratio, as detected by GC-MS. Overexpression of CREMtau and ICER has little effect on the Hmgcr proximal promoter while they influence expression from the CYP51 promoter. Our data indicate that Crem-dependent regulation of Cyp51 in the liver results in circadian expression of this gene. We propose that cAMP signaling might generally be involved in the circadian regulation of cholesterol synthesis on the periphery.
Acimovic
Jure
J
Centre for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, Ljubljana, Slovenia.
Fink
Martina
M
Pompon
Denis
D
Bjorkhem
Ingemar
I
Hirayama
Jun
J
Sassone-Corsi
Paolo
P
Golicnik
Marko
M
Rozman
Damjana
D
D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis*; D002940:Circadian Rhythm / Q000235:genetics; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D005786:Gene Expression Regulation; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000096:biosynthesis*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D058886:Sterol 14-Demethylase
D020033:Protein Isoforms; D051786:Cyclic AMP Response Element Modulator; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; C548415:Cyp51 protein, mouse; D058886:Sterol 14-Demethylase; D006904:Hydroxymethylglutaryl-CoA Synthase