Metabolic labeling unveils alterations in the turnover of HDL-associated proteins during diabetes progression in mice
Metabolic labeling unveils alterations in the turnover of HDL-associated proteins during diabetes progression in mice
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DOI：
10.1152/ajpendo.00158.2022
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发表时间：
2022-12-01
影响因子：
5.1
通讯作者：
Kasumov，Takhar
中科院分区：
文献类型：
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作者：
Sadana，Prabodh;Edler，Melissa;Kasumov，Takhar
糖尿病病理生理和并发症的几个方面是由高血糖引起的血浆蛋白结构和功能的改变引起的。此外，胰岛素通过影响各种组织中蛋白质的合成和降解，对蛋白质代谢有显著影响。为了了解进行性高血糖对血浆蛋白的作用，本研究采用重水代谢标记法，在HFD C57BL/6J小鼠的5 - 8周内，测量了对照组（鼠粮）、糖尿病前期[高脂饮食（HFD） 8周]或糖尿病[高脂饮食（HFD） 8周]小鼠高密度脂蛋白（HDL）相关蛋白的周转率。与对照组小鼠相比，HFD和HFD + STZ小鼠的空腹血糖水平分别在糖尿病前期和糖尿病范围内升高。此外，HFD和HFD + STZ小鼠肝脏甘油三酯（TG）水平、血浆总胆固醇和血浆TG水平均升高。采用蛋白质组动力学方法对40种蛋白的动力学进行了定量分析，结果表明，与对照组相比，糖尿病前期小鼠的hdl相关蛋白的分数合成率（FSR）有所增加，而糖尿病前期小鼠的FSR则有所降低。通路分析显示，改变周转率的蛋白质参与急性期反应、脂质代谢和凝血。总之，糖尿病前期和糖尿病对HDL蛋白的周转率有不同的影响。这些发现表明，HDL蛋白质组动力学的早期失调可以为这些条件下蛋白质水平的变化提供机制见解。新的和值得注意的是，这项研究首次研究了糖尿病前期和糖尿病小鼠中糖尿病疾病进展过程中渐进性高血糖对hdl相关蛋白动力学的作用。我们的研究结果表明，与对照小鼠相比，糖尿病前期小鼠的高密度脂蛋白相关蛋白的合成率增加，而糖尿病小鼠的合成率则降低。这些动力学变化有助于阐明糖尿病疾病进展过程中蛋白质水平改变和高密度脂蛋白功能障碍的机制。
Several aspects of diabetes pathophysiology and complications result from hyperglycemia-induced alterations in the structure and function of plasma proteins. Furthermore, insulin has a significant influence on protein metabolism by affecting both the synthesis and degradation of proteins in various tissues. To understand the role of progressive hyperglycemia on plasma proteins, in this study, we measured the turnover rates of high-density lipoprotein (HDL)-associated proteins in control (chow diet), prediabetic [a high-fat diet (HFD) for 8 wk] or diabetic [HFD for 8 wk with low-dose streptozotocin (HFD + STZ) inweeks 5–8of HFD] C57BL/6J mice using heavy water (2H2O)-based metabolic labeling approach. Compared with control mice, HFD and HFD + STZ mice showed elevations of fasting plasma glucose levels in the prediabetic and diabetic range, respectively. Furthermore, the HFD and HFD + STZ mice showed increased hepatic triglyceride (TG) levels, total plasma cholesterol, and plasma TGs. The kinetics of 40 proteins were quantified using the proteome dynamics method, which revealed an increase in the fractional synthesis rate (FSR) of HDL-associated proteins in the prediabetic mice compared with control mice, and a decrease in FSR in the diabetic mice. The pathway analysis revealed that proteins with altered turnover rates were involved in acute-phase response, lipid metabolism, and coagulation. In conclusion, prediabetes and diabetes have distinct effects on the turnover rates of HDL proteins. These findings suggest that an early dysregulation of the HDL proteome dynamics can provide mechanistic insights into the changes in protein levels in these conditions.NEW & NOTEWORTHYThis study is the first to examine the role of gradual hyperglycemia during diabetes disease progression on HDL-associated protein dynamics in the prediabetes and diabetic mice. Our results show that the fractional synthesis rate of HDL-associated proteins increased in the prediabetic mice whereas it decreased in the diabetic mice compared with control mice. These kinetic changes can help to elucidate the mechanism of altered protein levels and HDL dysfunction during diabetes disease progression.