Defining a relationship between dietary fatty acids and the cytochrome P450 system in a mouse model of fatty liver disease

Authors

Monika Gonzalez, Albany Medical College
Whitney Sealls, Albany Medical College
Elliot D. Jesch, University of Nebraska-Lincoln
M. Julia Brosnan, Albany Medical College
Istvan Ladunga, University of Nebraska at LincolnFollow
Xinxin Ding, State University of New York
Paul N. Black, Albany Medical CollegeFollow
Concetta C. DiRusso, Center for Metabolic Disease, Ordway Research InstituteFollow

ORCID IDs

Istvan Ladunga

Date of this Version

2011

Citation

Physiol Genomics. 2011 Feb; 43(3): 121–135.

Comments

Copyright © 2011 the American Physiological Society

Abstract

Liver-specific ablation of cytochrome P450 reductase in mice (LCN) results in hepatic steatosis that can progress to steatohepatitis characterized by inflammation and fibrosis. The specific cause of the fatty liver phenotype is poorly understood but is hypothesized to result from elevated expression of genes encoding fatty acid synthetic genes. Since expression of these genes is known to be suppressed by polyunsaturated fatty acids, we performed physiological and genomics studies to evaluate the effects of dietary linoleic and linolenic fatty acids (PUFA) or arachidonic and decosahexaenoic acids (HUFA) on the hepatic phenotypes of control and LCN mice by comparison with a diet enriched in saturated fatty acids. The dietary interventions with HUFA reduced the fatty liver phenotype in livers of LCN mice and altered the gene expression patterns in these livers to more closely resemble those of control mice. Importantly, the expression of genes encoding lipid pathway enzymes were not different between controls and LCN livers, indicating a strong influence of diet over POR genotype. These analyses highlighted the impact of POR ablation on expression of genes encoding P450 enzymes and proteins involved in stress and inflammation. We also found that livers from animals of both genotypes fed diets enriched in PUFA had gene expression patterns more closely resembling those fed diets enriched in saturated fatty acids. These results strongly suggest only HUFA supplied from an exogenous source can suppress hepatic lipogenesis.