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Flavin containing monooxygenase 5 and endogenous metabolism

Gonzalez Malagon, S.G.; (2012) Flavin containing monooxygenase 5 and endogenous metabolism. Doctoral thesis, UCL (University College London).

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Abstract

To gain insights into the endogenous role of flavin-containing monooxygenase 5 (FMO5), the phenotype of male Fmo5 knockout mice was investigated. Up to 22 weeks of age Fmo5 -/- male mice have a similar body weight to wild-type animals. However, from 30-weeks of age the knockout mice have a reduced weight gain. Gonadal fat deposits are smaller in young (4-week old), but are greatly reduced in older knockout animals. Despite the lower body weight and reduced fat deposits, the older Fmo5 -/- mice show increased food intake. They do not exhibit increased activity but have an increased metabolic rate. Proteomic results of 30-week old mice revealed downregulation of cytosolic malic enzyme, which is important in the production of NADPH, a major cofactor required in the biosynthesis of fatty acids. Older mice have reduced plasma glucose and the distribution of glycogen in the liver of the Fmo5 -/-mice is changed. Plasma total cholesterol, HDL and LDL are reduced in the knockout mice from 15 weeks of age. The rate limiting enzymes of cholesterol metabolism were analysed in 30-week old mice by real time PCR. The mRNAs for HMG CoA reductase and Squalene Synthase were increased, suggesting that the feedback mechanism of cholesterol regulation is responsive. However, the level of cholesterol cannot be increased to that of wild type mice. HMG CoA synthase protein, but not mRNA, is down-regulated in the Fmo5-/- mice. This suggests a restriction of a substrate for cholesterol biosynthesis. The results of the studies on the knockout mice reveal that FMO5 plays a role in regulating endogenous fat and cholesterol metabolism. The glucose phenotype might be a consequence of the inability to maintain long-term energy storage deposits. The exact mechanism of how FMO5 is involved in the fat and cholesterol metabolism is not known.

Type:Thesis (Doctoral)
Title:Flavin containing monooxygenase 5 and endogenous metabolism
Language:English
Additional information:Permission for digitisation not received
UCL classification:UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Structural and Molecular Biology

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