The Disruption of Hepatic Cytochrome P450 Reductase Alters Mouse Lipid Metabolism

To elucidate the role of hepatic cytochrome P450 oxidoreductase (POR) in lipid metabolism, we
characterized perturbations in lipid homeostasis in a mouse model deficient in liver POR. Using an
integrative approach in which transcriptomics, lipidomics, and various bioinformatic algorithms were
employed, a disruption in liver lipid mobilization, oxidation, and electron transport functions were
identified. Analyzing the promoters of genes in these biological processes identified common binding
motifs for nuclear receptors sensitive to lipid status, while Srebp-1c binding sites were only identified
in genes involved in lipid metabolism. POR-null mice had drastic increases in hepatic lipid content
(diacylglycerols, triacylglycerols, phosphatidylcholine, and cholesterol esters) and a specific enrichment
in n-7 and n-9 monounsaturated fatty acids (FAs). It was found that while transporters involved in
peroxisomal FA oxidation were induced, mitochondrial oxidation appeared to be more tightly controlled,
supporting the increase in monounsaturated FAs. Genes coding for hepatic transporters were
differentially expressed, where lipid uptake was induced and efflux repressed, indicating that in the
absence of hepatic POR the liver serves as a lipid reservoir. Furthermore, while significant changes in
intestinal gene expression were found in POR-deficient mice, only minor changes to plasma and
intestinal lipid content were observed. Thus, while liver POR plays an important role regulating gene
expression and lipid metabolism locally, the hepatic deficiency of this enzyme reverberates throughout
the biological system and produces a coordinated response to the low levels of circulating cholesterol
and bile.
Keywords: Oxidoreductase • lipidomics • systems biology • promoter analysis • microarray • knock-out