The disruption of hepatic cytochrome P450 reductase afters mouse lipid metabolism

David M. Mutch, Bernward Klocke, Peter Morrison, Carol A. Murray, Colin J. Henderson, Martin Seifert, Gary Williamson

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    Abstract

    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.

    Original languageEnglish
    Pages (from-to)3976-3984
    Number of pages9
    JournalJournal of Proteome Research
    Volume6
    Issue number10
    DOIs
    Publication statusPublished - Oct 2007

    Cite this

    Mutch, D. M., Klocke, B., Morrison, P., Murray, C. A., Henderson, C. J., Seifert, M., & Williamson, G. (2007). The disruption of hepatic cytochrome P450 reductase afters mouse lipid metabolism. Journal of Proteome Research, 6(10), 3976-3984. https://doi.org/10.1021/pr0700448