title: Defining a relationship between dietary fatty acids and the cytochrome P450 system in a mouse model of fatty liver disease.
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.
authors.affiliation: Center for Metabolic Disease, Ordway Research Institute and Center for Cardiovascular Science, Albany Medical College, Albany, New York, USA.
authors.forename: Monika
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Whitney
authors.initials: W
authors.lastname: Sealls
authors.forename: Elliot D
authors.initials: ED
authors.lastname: Jesch
authors.forename: M Julia
authors.initials: MJ
authors.lastname: Brosnan
authors.forename: Istvan
authors.initials: I
authors.lastname: Ladunga
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ding
authors.forename: Paul N
authors.initials: PN
authors.lastname: Black
authors.forename: Concetta C
authors.initials: CC
authors.lastname: DiRusso
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000008:administration & dosage / Q000494:pharmacology*; D005234:Fatty Liver / Q000097:blood / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005247:Feeding Behavior / Q000187:drug effects; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D008055:Lipids / Q000032:analysis; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D016133:Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D005227:Fatty Acids; D008055:Lipids; D014280:Triglycerides; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol