Unknown,Transcriptomics,Genomics,Proteomics

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Effect of dietary fat and cholesterol on hepatic gene expression of liver-specific Cyp51 knockout male and female mice


ABSTRACT: Cholesterol is one of the key molecules in mammals and the most striking examples of its deficiency are the inborn errors of cholesterol biosynthesis that manifest in severe whole body phenotypes. Liver, the principal site of cholesterol homeostasis, has rarely been investigated in these defects. We thus focused on the hepatocyte-specific deletion of lanosterol 14α-demethylase (CYP51) catalyzing the rate-limiting step in the post-squalene part of cholesterol synthesis. Liver-specific Cyp51 KO (LKO or K) and littermate control (LWT or W) mice (129/Pas (10%) × C57BL/6J (90%)) of both sexes (F and M) were investigated in the context of different nutritional availability of fat and cholesterol (standard laboratory diet without cholesterol (LFnC or L), high-fat diet without cholesterol (HFnC or H) and high-fat diet with cholesterol (HFC or C) due to the known sexual dimorphism in hepatic gene expression, where lipid metabolic pathways are among the most biased. 3 condition experimental design: 3 diets (LFnC or L, HFnC or H, HFC or C), 2 genotypes (LWT or W, LKO or K), 2 sexes (F, M), 3 biological replicates per condition, 36 mice altogether

ORGANISM(S): Mus musculus

SUBMITTER: Peter Juvan 

PROVIDER: E-GEOD-58271 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Lessons from hepatocyte-specific Cyp51 knockout mice: impaired cholesterol synthesis leads to oval cell-driven liver injury.

Lorbek Gregor G   Perše Martina M   Jeruc Jera J   Juvan Peter P   Gutierrez-Mariscal Francisco M FM   Lewinska Monika M   Gebhardt Rolf R   Keber Rok R   Horvat Simon S   Björkhem Ingemar I   Rozman Damjana D  

Scientific reports 20150305


We demonstrate unequivocally that defective cholesterol synthesis is an independent determinant of liver inflammation and fibrosis. We prepared a mouse hepatocyte-specific knockout (LKO) of lanosterol 14α-demethylase (CYP51) from the part of cholesterol synthesis that is already committed to cholesterol. LKO mice developed hepatomegaly with oval cell proliferation, fibrosis and inflammation, but without steatosis. The key trigger was reduced cholesterol esters that provoked cell cycle arrest, se  ...[more]

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