Hu Li-Tian, Zhu Bing-Lin, Lai Yu-Jie, Long Yan, Zha Jing-Si, Hu Xiao-Tong, Zhang John H, Chen Guo-Jun
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China; Department of Neurology, Nanchong Central Hospital, The Second Clinical College of North Sichuan Medical College, Nanchong 637000, Sichuan, China.
Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
Biochem Biophys Res Commun. 2017 Apr 29;486(2):492-498. doi: 10.1016/j.bbrc.2017.03.069. Epub 2017 Mar 18.
HMGCS2 (mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2) is a control enzyme in ketogenesis. The mitochondrial localization and interaction with APP (β-amyloid precursor protein) suggest that HMGCS2 may play a role in the pathophysiology of AD (Alzheimer's disease). Here we report that overexpression of HMGCS2 decreased levels of APP and related CTFs (carboxy-terminal fragments), which was largely prevented by an autophagic inhibitor chloroquine. In addition, HMGCS2 enhancement of autophagic marker LC3II was diminished by rapamycin, an inhibitor of mechanistic target of rapamycin. Moreover, deprivation of EBSS (Earle's Balanced Salt Solution) significantly augmented the effect of HMGCS2 on LC3II, while acetoacetate reversed the reduction of LC3II, APP and CTFs which was induced by HMGCS2 knockdown. In the presence of acetoacetate, rapamycin failed to induce further increase of LC3II, which mimicked the effect of HMGCS2 overexpression. Finally, HMGCS2 enhanced the antioxidant response. Collectively, HMGCS2 shares with ketone bodies common features in autophagic clearance of APP and CTFs, suggesting that ketone bodies play an important role in HMGCS2 regulation of the autophagy.
HMGCS2（线粒体3-羟基-3-甲基戊二酰辅酶A合酶2）是生酮作用中的一种关键酶。其线粒体定位以及与APP（β-淀粉样前体蛋白）的相互作用表明，HMGCS2可能在阿尔茨海默病（AD）的病理生理学中发挥作用。在此我们报告，HMGCS2的过表达降低了APP及相关CTFs（羧基末端片段）的水平，而这在很大程度上被自噬抑制剂氯喹所阻止。此外，雷帕霉素（一种雷帕霉素作用靶点的抑制剂）减弱了HMGCS2对自噬标志物LC3II的增强作用。而且，剥夺Earle平衡盐溶液（EBSS）显著增强了HMGCS2对LC3II的作用，而乙酰乙酸逆转了由HMGCS2敲低所诱导的LC3II、APP和CTFs的减少。在存在乙酰乙酸的情况下，雷帕霉素未能诱导LC3II进一步增加，这模拟了HMGCS2过表达的效果。最后，HMGCS2增强了抗氧化反应。总体而言，HMGCS2与酮体在APP和CTFs的自噬清除方面具有共同特征，表明酮体在HMGCS2对自噬的调节中起重要作用。
