Abstract

The ubiquitin–proteasome system (UPS) and autophagy are two major intracellular proteolytic systems that are closely associated with each other. Because UPS and autophagy are involved in the clearance of oxidised and/or aggregated proteins, it would be logical to assume that alterations in proteolysis would accompany pathological conditions. Indeed, both systems are themselves susceptible to oxidative modification and therefore could be a prominent target of reactive oxygen species (ROS). Oxidative stress appears to be a common underlying factor in the development of and the pathogenesis of various metabolic diseases, including non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). Recent studies, using obesity and hyperglycaemia model mice, reported that both UPS and autophagy systems are inhibited in these mice and that this inhibition is accompanied by lipid accumulation, insulin resistance, and tissue damage. However, the detailed molecular mechanisms that are responsible for regulating intracellular proteolysis in metabolic diseases are not well understood. In the current review, we discuss the correlation between oxidative stress, defective proteolysis, and metabolic diseases. An understanding of how ROS affects intracellular proteolysis may provide new perspectives on the development of and control of diseases.

摘要

泛素-蛋白酶体系统 (UPS) 和自噬是两个主要的细胞内蛋白水解系统，彼此密切相关。因为 UPS 和自噬参与氧化和/或聚集蛋白的清除，所以假设蛋白水解的改变会伴随病理状况是合乎逻辑的。事实上，这两个系统本身都容易受到氧化修饰，因此可能是活性氧 (ROS) 的重要目标。氧化应激似乎是包括非酒精性脂肪肝 (NAFLD) 和 2 型糖尿病 (T2D) 在内的各种代谢疾病的发展和发病机制中常见的潜在因素。最近的研究，使用肥胖和高血糖模型小鼠，据报道，UPS 和自噬系统在这些小鼠中都受到抑制，并且这种抑制伴随着脂质积累、胰岛素抵抗和组织损伤。然而，负责调节代谢疾病中细胞内蛋白水解的详细分子机制尚不清楚。在当前的综述中，我们讨论了氧化应激、蛋白水解缺陷和代谢疾病之间的相关性。了解 ROS 如何影响细胞内蛋白水解可能为疾病的发展和控制提供新的视角。我们讨论氧化应激、蛋白水解缺陷和代谢疾病之间的相关性。了解 ROS 如何影响细胞内蛋白水解可能为疾病的发展和控制提供新的视角。我们讨论氧化应激、蛋白水解缺陷和代谢疾病之间的相关性。了解 ROS 如何影响细胞内蛋白水解可能为疾病的发展和控制提供新的视角。