Department of Basic Medical Science, College of Medicine, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar.
Biomedical & Pharmaceutical Research Unit, QU Health, Qatar University, P.O. Box 2713, Doha, Qatar.
Glycoconj J. 2021 Jun;38(3):331-340. doi: 10.1007/s10719-021-09980-0. Epub 2021 Mar 1.
The reactive dicarbonyl metabolite, methylglyoxal (MG), is increased in obesity and diabetes and is implicated in the development of insulin resistance, type 2 diabetes mellitus and vascular complications of diabetes. Dicarbonyl stress is the metabolic state of abnormal high MG concentration. MG is an arginine-directed glycating agent and precursor of the major advanced glycation endproduct, arginine-derived hydroimidazolone MG-H1. MG-H1 is often formed on protein surfaces and an uncharged hydrophobic residue, inducing protein structural distortion and misfolding. Recent studies indicate that dicarbonyl stress in human endothelial cells and fibroblasts in vitro induced a proteomic response consistent with activation of the unfolded protein response (UPR). The response included: increased abundance of heat shock proteins and ubiquitin ligases catalysing the removal of proteins with unshielded surface hydrophobic patches and formation of polyubiquitinated chains to encapsulate misfolded proteins; and increased low grade inflammation. Activation of the UPR is implicated in insulin resistance. An effective strategy to counter increased MG is inducing increased expression of glyoxalase-1 (Glo1). An optimized inducer of Glo1 expression, trans-resveratrol and hesperetin combination, normalized increased MG concentration, corrected insulin resistance and decreased low grade inflammation in overweight and obese subjects. We propose that dicarbonyl stress, through increased formation of MG-glycated proteins, may be an important physiological stimulus of the UPR and Glo1 inducers may provide a route to effective suppression and therapy. With further investigation and validation, this may provide key new insight into physiological activators of the UPR and association with dicarbonyl stress.
活性二羰基代谢物甲基乙二醛（MG）在肥胖和糖尿病中增加，并与胰岛素抵抗、2 型糖尿病和糖尿病血管并发症的发展有关。二羰基应激是异常高 MG 浓度的代谢状态。MG 是精氨酸定向糖基化剂和主要的晚期糖基化终产物精氨酸衍生的氢咪唑啉酮 MG-H1 的前体。MG-H1 通常在蛋白质表面形成，并带有不带电荷的疏水性残基，诱导蛋白质结构扭曲和错误折叠。最近的研究表明，体外人内皮细胞和成纤维细胞的二羰基应激诱导了与未折叠蛋白反应（UPR）激活一致的蛋白质组反应。该反应包括：热休克蛋白和泛素连接酶的丰度增加，这些酶催化去除具有无屏蔽表面疏水性斑块的蛋白质，并形成多泛素化链以包裹错误折叠的蛋白质；以及低度炎症增加。UPR 的激活与胰岛素抵抗有关。一种有效的对抗 MG 增加的策略是诱导甘油醛-1（Glo1）的表达增加。Glo1 表达的优化诱导剂，反式白藜芦醇和橙皮苷的组合，使超重和肥胖者的 MG 浓度增加正常化，纠正胰岛素抵抗，降低低度炎症。我们提出，二羰基应激通过增加 MG 糖化蛋白的形成，可能是 UPR 的重要生理刺激因素，二羰基应激诱导剂可能为有效的抑制和治疗提供途径。随着进一步的研究和验证，这可能为 UPR 的生理激活剂及其与二羰基应激的关联提供关键的新见解。
