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

Scientific Reports
Gregor LorbekDamjana Rozman

Abstract

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.

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Citations

Nov 8, 2015·Experimental Gerontology·Aleksandar Z BaburskiTatjana S Kostic
Jul 6, 2016·Pharmacogenomics·Gregor LorbekDamjana Rozman
Jul 5, 2018·Expert Opinion on Drug Metabolism & Toxicology·Cene SkubicDamjana Rozman
Mar 30, 2016·Molecular and Cellular Biology·Yuanming ChengYing Feng
Feb 21, 2018·Biomedit︠s︡inskai︠a︡ khimii︠a︡·P V ErshovA S Ivanov
Jul 18, 2017·Frontiers in Pharmacology·Tadeja ReženDamjana Rozman
Feb 6, 2017·Scientific Reports·Yurina ShishidoKen-Ichirou Morohashi
May 1, 2018·Frontiers in Physiology·Tanja Cvitanović TomašDamjana Rozman
Jan 21, 2021·International Journal of Molecular Sciences·Kaja Blagotinšek CokanTadeja Režen
Nov 7, 2020·Biochimica Et Biophysica Acta. Molecular and Cell Biology of Lipids·Eva KočarDamjana Rozman

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