Department of Biophysics, Center for Human and Molecular Biology (ZHMB), Saarland University, Homburg, Germany; Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, SP, Brazil.
Institute for Clinical and Experimental Surgery, Saarland University, Homburg, Germany.
Free Radic Biol Med. 2021 Jan;162:1-13. doi: 10.1016/j.freeradbiomed.2020.11.023. Epub 2020 Nov 27.
Modern lifestyles, including lack of physical activity and poor nutritional habits, are driving the rapidly increasing prevalence of obesity and type 2 diabetes. Increased levels of free fatty acids (FFAs), particularly saturated FFAs, in obese individuals have been linked to pancreatic β-cell failure. This process, termed lipotoxicity, involves activation of several stress responses, including ER stress and oxidative stress. However, the molecular underpinnings and causal relationships between the disparate stress responses remain unclear. Here we employed transgenic mice, expressing a genetically-encoded cytosolic HO sensor, roGFP2-Orp1, to monitor dynamic changes in HO levels in pancreatic islets in response to chronic palmitate exposure. We identified a transient increase in HO levels from 4 to 8 h after palmitate addition, which was mirrored by a concomitant decrease in cellular NAD(P)H levels. Intriguingly, islets isolated from NOX2 knock-out mice displayed no HO transient upon chronic palmitate treatment. Furthermore, NOX2 knockout rescued palmitate-dependent impairment of insulin secretion, calcium homeostasis and viability. Chemical inhibition of NOX activity protected islets from palmitate-induced impairment in insulin secretion, however had no detectable impact upon the induction of ER stress. In summary, our results reveal that transient NOX2-dependent HO production is a likely cause of early palmitate-dependent lipotoxic effects.
现代生活方式，包括缺乏身体活动和不良的营养习惯，正在推动肥胖症和 2 型糖尿病的患病率迅速上升。肥胖个体中游离脂肪酸（FFAs）水平升高，特别是饱和 FFAs，与胰腺β细胞衰竭有关。这个过程被称为脂毒性，涉及到几种应激反应的激活，包括内质网应激和氧化应激。然而，不同应激反应之间的分子基础和因果关系仍不清楚。在这里，我们使用表达遗传编码胞质 HO 传感器 roGFP2-Orp1 的转基因小鼠，监测慢性棕榈酸盐暴露后胰岛中 HO 水平的动态变化。我们发现，棕榈酸盐添加后 4 至 8 小时 HO 水平短暂增加，同时细胞 NAD(P)H 水平相应降低。有趣的是，NOX2 敲除小鼠的胰岛在慢性棕榈酸盐处理后没有 HO 短暂增加。此外，NOX2 敲除可挽救棕榈酸盐依赖性胰岛素分泌、钙稳态和活力的损伤。NOX 活性的化学抑制可防止胰岛受到棕榈酸盐诱导的胰岛素分泌损伤，但对 ER 应激的诱导没有明显影响。总之，我们的结果表明，短暂的 NOX2 依赖性 HO 产生可能是早期棕榈酸盐依赖性脂毒性作用的原因。
