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.
Highlights
We demonstrate unequivocally that defective cholesterol synthesis is an independent determinant of liver inflammation and fibrosis
We focused on lanosterol 14a-demethylase (CYP51) from the late part of the cholesterol synthesis pathway that is already committed to cholesterol[15]
CYP51 immunohistochemistry (Fig. 1c) showed singular or small foci of stained periportal hepatocytes that potentially originated from the oval cell compartment as was demonstrated by others[19]
Summary
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 14a-demethylase (CYP51) from the part of cholesterol synthesis that is already committed to cholesterol. 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. It is crucial to determine the role of hepatocyte cholesterol synthesis in the liver by leaving the isoprenoid pathway intact. It is interesting to question whether cholesterol synthesis disharmony is responsible for sex dependent liver pathophysiology
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