State Key Laboratory of Natural Medicines and School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.
Int J Mol Sci. 2020 Apr 9;21(7):2612. doi: 10.3390/ijms21072612.
Metabolic syndrome (MetS) is a constellation of metabolic derangements, including central obesity, insulin resistance, hypertension, glucose intolerance, and dyslipidemia. The pathogenesis of MetS has been intensively studied, and now many factors are recognized to contribute to the development of MetS. Among these, trace elements influence the structure of proteins, enzymes, and complex carbohydrates, and thus an imbalance in trace elements is an independent risk factor for MetS. The molecular link between trace elements and metabolic homeostasis has been established, and peroxisome proliferator-activated receptors (PPARs) have appeared as key regulators bridging these two elements. This is because on one hand, PPARs are actively involved in various metabolic processes, such as abdominal adiposity and insulin sensitivity, and on the other hand, PPARs sensitively respond to changes in trace elements. For example, an iron overload attenuates hepatic mRNA expression of ; zinc supplementation is considered to recover the DNA-binding activity of PPAR-α, which is impaired in steatotic mouse liver; selenium administration downregulates mRNA expression of , thereby improving lipid metabolism and oxidative status in the liver of high-fat diet (HFD)-fed mice. More importantly, PPARs' expression and activity are under the control of the circadian clock and show a robust 24 h rhythmicity, which might be the reasons for the side effects and the clinical limitations of trace elements targeting PPARs. Taken together, understanding the casual relationships among trace elements, PPARs' actions, and the pathogenesis of MetS is of great importance. Further studies are required to explore the chronopharmacological effects of trace elements on the diurnal oscillation of PPARs and the consequent development of MetS.
代谢综合征（Metabolic syndrome，MetS）是一组代谢紊乱的综合征，包括中心性肥胖、胰岛素抵抗、高血压、葡萄糖耐量异常和血脂异常。MetS 的发病机制已得到深入研究，现在许多因素被认为有助于 MetS 的发展。在这些因素中，微量元素影响蛋白质、酶和复合碳水化合物的结构，因此微量元素失衡是 MetS 的一个独立危险因素。微量元素与代谢稳态之间的分子联系已经建立，过氧化物酶体增殖物激活受体（peroxisome proliferator-activated receptors，PPARs）作为连接这两个因素的关键调节因子出现。这是因为一方面，PPARs 积极参与各种代谢过程，如腹部肥胖和胰岛素敏感性，另一方面，PPARs 对微量元素的变化敏感。例如，铁过载会减弱肝脏中 的 mRNA 表达；锌补充被认为可以恢复在脂肪肝小鼠肝脏中受损的 PPAR-α 的 DNA 结合活性；硒给药下调 的 mRNA 表达，从而改善高脂肪饮食（high-fat diet，HFD）喂养小鼠肝脏中的脂质代谢和氧化状态。更重要的是，PPARs 的表达和活性受昼夜节律的控制，并表现出强大的 24 小时节律性，这可能是微量元素靶向 PPARs 的副作用和临床局限性的原因。总之，了解微量元素、PPARs 作用与 MetS 发病机制之间的因果关系非常重要。需要进一步研究以探讨微量元素对 PPARs 昼夜节律性波动的chronopharmacological 作用及其对 MetS 的发展的影响。
