Department of Structural and Molecular Biology, University College London, London, United Kingdom.
School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom.
PLoS One. 2023 Jun 2;18(6):e0286692. doi: 10.1371/journal.pone.0286692. eCollection 2023.
Flavin-containing monooxygenase 5 (FMO5) is a member of the FMO family of proteins, best known for their roles in the detoxification of foreign chemicals and, more recently, in endogenous metabolism. We have previously shown that Fmo5-/- mice display an age-related lean phenotype, with much reduced weight gain from 20 weeks of age. The phenotype is characterized by decreased fat deposition, lower plasma concentrations of glucose, insulin and cholesterol, higher glucose tolerance and insulin sensitivity, and resistance to diet-induced obesity. In the present study we report the use of metabolomic and transcriptomic analyses of livers of Fmo5-/- and wild-type mice to identify factors underlying the lean phenotype of Fmo5-/- mice and gain insights into the function of FMO5. Metabolomics was performed by the Metabolon platform, utilising ultrahigh performance liquid chromatography-tandem mass spectroscopy. Transcriptomics was performed by RNA-Seq and results analysed by DESeq2. Disruption of the Fmo5 gene has wide-ranging effects on the abundance of metabolites and expression of genes in the liver. Metabolites whose concentration differed between Fmo5-/- and wild-type mice include several saturated and monounsaturated fatty acids, complex lipids, amino acids, one-carbon intermediates and ADP-ribose. Among the genes most significantly and/or highly differentially expressed are Apoa4, Cd36, Fitm1, Hspa5, Hyou1, Ide, Me1 and Mme. The results reveal that FMO5 is involved in upregulating the NRF2-mediated oxidative stress response, the unfolded protein response and response to hypoxia and cellular stress, indicating a role for the enzyme in adaptation to oxidative and metabolic stress. FMO5 also plays a role in stimulating a wide range of metabolic pathways and processes, particularly ones involved in lipid homeostasis, the uptake and metabolism of glucose, the generation of cytosolic NADPH, and in one-carbon metabolism. The results predict that FMO5 acts by stimulating the NRF2, XBP1, PPARA and PPARG regulatory pathways, while inhibiting STAT1 and IRF7 pathways.
黄素单加氧酶 5（FMO5）是黄素单加氧酶家族蛋白的成员，以其在解毒外来化学物质中的作用而闻名，最近又因其在内源性代谢中的作用而闻名。我们之前曾表明，Fmo5-/- 小鼠表现出与年龄相关的瘦表型，从 20 周龄开始体重增加明显减少。该表型的特征是脂肪沉积减少，血浆葡萄糖、胰岛素和胆固醇浓度降低，葡萄糖耐量和胰岛素敏感性增加，以及对饮食诱导肥胖的抵抗力。在本研究中，我们报告了使用代谢组学和转录组学分析 Fmo5-/- 和野生型小鼠的肝脏，以确定 Fmo5-/- 小鼠瘦表型的基础因素，并深入了解 FMO5 的功能。代谢组学是通过利用超高液相色谱-串联质谱的代谢组学平台进行的。转录组学是通过 RNA-Seq 进行的，结果通过 DESeq2 进行分析。Fmo5 基因的破坏对肝脏中代谢物和基因的丰度有广泛的影响。在 Fmo5-/- 和野生型小鼠之间浓度不同的代谢物包括几种饱和和单不饱和脂肪酸、复合脂质、氨基酸、一碳中间体和 ADP-核糖。在表达差异最显著和/或高度差异的基因中，Apoa4、Cd36、Fitm1、Hspa5、Hyou1、Ide、Me1 和 Mme 基因最为显著。结果表明，FMO5 参与上调 NRF2 介导的氧化应激反应、未折叠蛋白反应以及对缺氧和细胞应激的反应，表明该酶在适应氧化和代谢应激中起作用。FMO5 还在刺激广泛的代谢途径和过程中发挥作用，特别是那些涉及脂质稳态、葡萄糖摄取和代谢、细胞质 NADPH 的产生以及一碳代谢的途径和过程。结果预测，FMO5 通过刺激 NRF2、XBP1、PPARA 和 PPARG 调节途径，同时抑制 STAT1 和 IRF7 途径发挥作用。
