Envirome Institute, Department of Medicine, University of Louisville, Louisville, KY, USA; Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, KY, USA.
Envirome Institute, Department of Medicine, University of Louisville, Louisville, KY, USA; Diabetes and Obesity Center, Department of Medicine, University of Louisville, Louisville, KY, USA.
Chem Biol Interact. 2019 Jun 1;306:104-109. doi: 10.1016/j.cbi.2019.04.014. Epub 2019 Apr 15.
Autophagy is a dynamic recycling process that eliminates damaged proteins and cellular organelles to maintain cellular homeostasis. Aldose reductase (AR) catalyzes conversion of glucose to sorbitol. It also catalyzes the reduction of a broad array of saturated and unsaturated aldehydes. Recently we demonstrated that deletion of AR promotes pathological cardiac remodeling via excessive autophagy; however, the role of AR in starvation-induced autophagy has not been determined. To determine the role of AR in starvation-induced autophagy, WTC57/Bl6 mice were pretreated with the AR inhibitor sorbinil (0.2 g/L for 48 h) in drinking water, followed by 24 h fasting. We found that the sorbinil pretreatment in fed mice did not affect blood glucose levels, whereas, it decreased the blood glucose levels in fasting mice. In comparison with fed mice, the LC3II formation and LCII/LCI ratio were increased in the fasted mice hearts and sorbinil pretreatment further enhanced LC3II formation and LC3II/LC3I ratios in these hearts. Fasting-induced autophagy coincided with AMPK activation in the sorbinil pretreated fasted mice hearts. Autophagy and activation of AMPK was also induced in the gastrocnemius skeletal muscle of sorbinil pre-treated fasted mice. Induction of autophagy in the cardiac tissues of sorbinil pretreated fasted mice was accompanied by increased clearance of 4-hydroxytrans-2-nonenal-protein adducts. Taken together, these results indicate that the inhibition of AR during fasting activates autophagic response, increases clearance of aldehyde-protein adducts, which could serve as a mechanism to maintain cellular homeostasis during starvation.
自噬是一种动态的回收过程，可消除受损的蛋白质和细胞细胞器，以维持细胞内环境的稳定。醛糖还原酶（AR）可催化葡萄糖转化为山梨醇。它还可催化多种饱和和不饱和醛的还原。最近我们证明，AR 的缺失通过过度自噬促进病理性心脏重构；然而，AR 在饥饿诱导的自噬中的作用尚未确定。为了确定 AR 在饥饿诱导的自噬中的作用，我们用 AR 抑制剂 sorbinil（饮用水中 0.2 g/L 预处理 48 h）预处理 WTC57/Bl6 小鼠，然后禁食 24 h。我们发现，喂食小鼠中的 sorbinil 预处理不会影响血糖水平，而在禁食小鼠中则降低了血糖水平。与喂食小鼠相比，禁食小鼠的心脏中 LC3II 形成和 LCII/LCI 比值增加，而 sorbinil 预处理进一步增强了这些心脏中的 LC3II 形成和 LC3II/LC3I 比值。禁食诱导的自噬与 sorbinil 预处理禁食小鼠心脏中 AMPK 的激活同时发生。禁食和 sorbinil 预处理也诱导了腓肠肌骨骼肌中的自噬。在 sorbinil 预处理禁食小鼠心脏中，自噬的诱导伴随着 4-羟基反-2-壬烯醛蛋白加合物的清除增加。总之，这些结果表明，在禁食期间抑制 AR 会激活自噬反应，增加醛蛋白加合物的清除，这可能是在饥饿期间维持细胞内环境稳定的一种机制。
