Li Jia-Min, Li Ling-Yu, Qin Xuan, Degrace Pascal, Demizieux Laurent, Limbu Samwel M, Wang Xin, Zhang Mei-Ling, Li Dong-Liang, Du Zhen-Yu
Laboratory of Aquaculture Nutrition and Environmental Health, School of Life Sciences, East China Normal University, Shanghai, China.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Front Physiol. 2018 May 9;9:509. doi: 10.3389/fphys.2018.00509. eCollection 2018.
Impaired mitochondrial fatty acid β-oxidation has been correlated with many metabolic syndromes, and the metabolic characteristics of the mammalian models of mitochondrial dysfunction have also been intensively studied. However, the effects of the impaired mitochondrial fatty acid β-oxidation on systemic metabolism in teleost have never been investigated. In the present study, we established a low-carnitine zebrafish model by feeding fish with mildronate as a specific carnitine synthesis inhibitor [0.05% body weight (BW)/d] for 7 weeks, and the systemically changed nutrient metabolism, including carnitine and triglyceride (TG) concentrations, fatty acid (FA) β-oxidation capability, and other molecular and biochemical assays of lipid, glucose, and protein metabolism, were measured. The results indicated that mildronate markedly decreased hepatic carnitine concentrations while it had no effect in muscle. Liver TG concentrations increased by more than 50% in mildronate-treated fish. Mildronate decreased the efficiency of liver mitochondrial β-oxidation, increased the hepatic mRNA expression of genes related to FA β-oxidation and lipolysis, and decreased the expression of lipogenesis genes. Mildronate decreased whole body glycogen content, increased glucose metabolism rate, and upregulated the expression of glucose uptake and glycolysis genes. Mildronate also increased whole body protein content and hepatic mRNA expression of mechanistic target of rapamycin (), and decreased the expression of a protein catabolism-related gene. Liver, rather than muscle, was the primary organ targeted by mildronate. In short, mildronate-induced hepatic inhibited carnitine synthesis in zebrafish caused decreased mitochondrial FA β-oxidation efficiency, greater lipid accumulation, and altered glucose and protein metabolism. This reveals the key roles of mitochondrial fatty acid β-oxidation in nutrient metabolism in fish, and this low-carnitine zebrafish model could also be used as a novel fish model for future metabolism studies.
线粒体脂肪酸β氧化受损与许多代谢综合征相关，线粒体功能障碍的哺乳动物模型的代谢特征也得到了深入研究。然而，线粒体脂肪酸β氧化受损对硬骨鱼全身代谢的影响从未被研究过。在本研究中，我们通过给斑马鱼喂食米多君（一种特异性肉碱合成抑制剂，剂量为0.05%体重/天）7周，建立了低肉碱斑马鱼模型，并测量了全身营养代谢的变化，包括肉碱和甘油三酯（TG）浓度、脂肪酸（FA）β氧化能力以及脂质、葡萄糖和蛋白质代谢的其他分子和生化检测指标。结果表明，米多君显著降低了肝脏肉碱浓度，但对肌肉没有影响。在米多君处理的斑马鱼中，肝脏TG浓度增加了50%以上。米多君降低了肝脏线粒体β氧化效率，增加了与FAβ氧化和脂解相关基因的肝脏mRNA表达，并降低了脂肪生成基因的表达。米多君降低了全身糖原含量，提高了葡萄糖代谢率，并上调了葡萄糖摄取和糖酵解基因的表达。米多君还增加了全身蛋白质含量和肝脏雷帕霉素靶蛋白（）的mRNA表达，并降低了与蛋白质分解代谢相关基因的表达。肝脏而非肌肉是米多君作用的主要器官。简而言之，米多君诱导的斑马鱼肝脏肉碱合成抑制导致线粒体FAβ氧化效率降低、脂质积累增加以及葡萄糖和蛋白质代谢改变。这揭示了线粒体脂肪酸β氧化在鱼类营养代谢中的关键作用，这种低肉碱斑马鱼模型也可作为未来代谢研究的新型鱼类模型。
