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Proteomic Consequences of the Deletion of Cytochrome P450 (CYP450) Reductase in Mice

ABSTRACT: Microsomal cytochrome P450 (CYP450) reductase enzymes play a major role in drug and xenobiotic metabolism. Mice which are deficient in hepatic CYP450 reductase serve as excellent models in understanding CYP450 drug metabolism and alterations in the underlying biology. A reversed-phase nano-bore UPLC-MS-based proteomic analysis, using an untargeted data independent approach (DIA), has been utilized for liver tissue extracts to evaluate differences between the proteomes of wild type (C57Bl6) and hepatic P450 reductase mice (HRNTM). Statistically curated, differential expressed protein groups highlighted a variety of molecular and biological functions, including binding and catalytic related activities. Pathway enrichment analysis resulted in perturbation of lipid and energy related pathways, which included bile acid biosynthesis, fatty acid omega oxidation and tricarbonic acid (TCA) cycle as examples.

INSTRUMENT(S): Synapt MS

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Lee Gethings

LAB HEAD: Lee Gethings

PROVIDER: PXD024420 | Pride | 2022-05-26

REPOSITORIES: Pride

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Project description:Elevated circulating lipid levels are known risk factors for cardiovascular diseases (CVD). In order to examine the effects of quercetin on hepatic lipid metabolism and detailed serum lipid profiles, mice received a mild-high-fat diet without (control) or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Gas chromatography and 1H nuclear magnetic resonance were used to measure quantitatively serum lipid profiles and whole genome microarray analysis was used to identify the responsible mechanisms in liver. There were no significant differences found in mean body weight, energy intake and hepatic lipid accumulation between the quercetin and control group. In serum of quercetin-fed mice, TG levels were decreased with 15%, poly unsaturated fatty acids (PUFA) were increased with 14% and saturated fatty acids were decreased. Palmitic acid, oleic acid, and linoleic acid were all decreased in quercetin-fed mice by 9-15%. Both palmitic acid and oleic acid can be oxidized by omega-oxidation. Indeed, gene expression profiling showed that quercetin increased hepatic lipid metabolism, especially omega-oxidation. At the gene level, this was reflected by the up regulation of cytochrome P450 (Cyp) 4a10, Cyp4a14, Cyp4a31 and Acyl-CoA thioesterase 3 (Acot3). Two relevant regulators, Cytochrome P450 oxidoreductase (Por, rate limiting for cytochrome P450s) and the transcription factor Constitutive androstane receptor (Car; official symbol Nr1i3) were also up regulated in the quercetin-fed mice. We conclude that quercetin intake increased hepatic lipid omega-oxidation and lowered corresponding circulating lipid levels, a process that may involve Por and Car, and results in a potential beneficial CVD preventive effect. Liver samples were obtained from 36 C57BL/6J male adult mice. All mice started with a three week adaptation phase, in which they were fed a mild-high-fat diet. 12 mice were sacrificed immediately after the adaptation phase (t=0). The other 24 mice received the mild-high-fat diet without (HF) or with supplementation of 0.33% (w/w) quercetin (HF-Q) for 12 weeks.

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Proteomic Consequences of the Deletion of Cytochrome P450 (CYP450) Reductase in Mice

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