Lessons from hepatocyte-specific Cyp51 knockout mice: impaired cholesterol synthesis leads to oval cell-driven liver injury.
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, senescence-associated secretory phenotype and ultimately the oval cell response, while elevated CYP51 substrates promoted the integrated stress response. In spite of the oval cell-driven fibrosis being histologically similar in both sexes, data indicates a female-biased down-regulation of primary metabolism pathways and a stronger immune response in males. Liver injury was ameliorated by dietary fats predominantly in females, whereas dietary cholesterol rectified fibrosis in both sexes. Our data place defective cholesterol synthesis as a focus of sex-dependent liver pathologies.
Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Gregor
G
Lorbek
Medical Experimental Centre, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Martina
M
Perše
Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Jera
J
Jeruc
Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Peter
P
Juvan
Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Francisco M
FM
Gutierrez-Mariscal
Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Monika
M
Lewinska
Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
Rolf
R
Gebhardt
Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia.
Rok
R
Keber
1] Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia [2] National Institute of Chemistry, Ljubljana, Slovenia.
Simon
S
Horvat
Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institute, Karolinska University Hospital, Huddinge, Sweden.
Ingemar
I
Björkhem
Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
Damjana
D
Rozman
D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002784:Cholesterol / Q000096:biosynthesis; D004041:Dietary Fats / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006505:Hepatitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism*; D006529:Hepatomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009928:Organ Specificity / Q000235:genetics; D012737:Sex Factors; D058886:Sterol 14-Demethylase / Q000235:genetics*
D001647:Bile Acids and Salts; D004041:Dietary Fats; D002784:Cholesterol; D058886:Sterol 14-Demethylase