Laboratory of Nutritional Biochemistry, Nagoya University, Nagoya 464-8601, Japan.
Department of Nutritional Science, Nagoya University of Arts and Sciences, Nisshin 470-0196, Japan.
J Biol Chem. 2019 Oct 18;294(42):15206-15217. doi: 10.1074/jbc.RA119.010328. Epub 2019 Sep 3.
Metabolic syndrome has become a global health challenge and was recently reported to be positively correlated with increased sucrose consumption. Mechanistic analyses of excess sucrose-induced progression of metabolic syndrome have been focused mainly on abnormal hepatic lipogenesis, and the exact contribution of excess sucrose to metabolic disorders remains controversial. Considering that carbohydrate and lipid metabolisms exhibit clear circadian rhythms, here we investigated the possible contribution of diurnal oscillations to responses of hepatic lipid metabolism to excess sucrose. We found that excess sucrose dose-dependently promotes fatty liver and hyperlipidemia in in rats fed a high-sucrose diet (HSD). We observed that excess sucrose enhances the oscillation amplitudes of the expression of clock genes along with the levels of hepatic lipid and carbohydrate metabolism-related mRNAs that increase lipogenesis. We did not observe similar changes in the levels of the transcription factors regulating the expression of these genes. This suggested that the excess sucrose-induced, circadian rhythm-dependent amplification of lipogenesis is post-transcriptionally regulated via the stability of metabolic gene transcripts. Of note, our findings also provide evidence that fructose causes some of the HSD-induced, circadian rhythm-dependent alterations in lipogenic gene expression. Our discovery of HSD-induced circadian rhythm-dependent alterations in lipogenesis at the post-transcriptional level may inform future studies investigating the complex relationships among sucrose uptake, circadian rhythm, and metabolic enzyme expression. Our findings could contribute to the design of chrono-nutritional interventions to prevent or manage the development of fatty liver and hyperlipidemia in sucrose-induced metabolic syndrome.
代谢综合征已成为全球健康挑战，最近有报道称其与蔗糖摄入量增加呈正相关。过量蔗糖引起代谢综合征进展的机制分析主要集中在异常的肝脂肪生成上，而过量蔗糖对代谢紊乱的确切贡献仍存在争议。鉴于碳水化合物和脂质代谢表现出明显的昼夜节律，我们在这里研究了昼夜节律波动对肝脏脂质代谢对过量蔗糖反应的可能贡献。我们发现，高蔗糖饮食（HSD）喂养的大鼠中，过量蔗糖会剂量依赖性地促进脂肪肝和高脂血症。我们观察到，过量蔗糖增强了时钟基因表达的振荡幅度，以及增加脂肪生成的肝脏脂质和碳水化合物代谢相关 mRNA 的水平。我们没有观察到调节这些基因表达的转录因子水平发生类似变化。这表明，过量蔗糖诱导的、昼夜节律依赖性的脂肪生成扩增是通过代谢基因转录本的稳定性进行的转录后调控。值得注意的是，我们的研究结果还提供了证据表明，果糖引起了 HSD 诱导的一些与昼夜节律相关的脂肪生成基因表达的改变。我们发现 HSD 诱导的脂肪生成在转录后水平上的昼夜节律依赖性改变，可能为未来研究蔗糖摄取、昼夜节律和代谢酶表达之间复杂关系提供信息。我们的研究结果可以为设计时间营养干预措施提供依据，以预防或管理蔗糖诱导的代谢综合征中的脂肪肝和高脂血症的发生。
