PDF(Pubmed)
Abstract：
Diabetic cardiomyopathy (DbCM) is characterized by diastolic dysfunction, which progresses into heart failure and aberrant electrophysiology in diabetic patients. Dyslipidemia in type 2 diabetic patients leads to the accumulation of lipid droplets (LDs) in cardiomyocytes and results in lipid toxicity which has been suggested to drive DbCM. It is aimed to explore potential pathways that may boost LDs degradation in DbCM and restore cardiac function. LDs accumulation resulted in an increase in lipid toxicity in DbCM hearts is confirmed. Microlipophagy pathway, rather than traditional macrolipophagy, is activated in DbCM hearts. RNA-Seq data and Rab7-CKO mice implicate that Rab7 is a major modulator of the microlipophagy pathway. Mechanistically, Rab7 is phosphorylated at Tyrosine 183, which allows the recruitment of Rab-interacting lysosome protein (Rilp) to proceed LDs degradation by lysosome. Treating DbCM mice with Rab7 activator ML-098 enhanced Rilp level and rescued the observed cardiac dysfunction. Overall, Rab7-Rilp-mediated microlipophagy may be a promising target in the treatment of lipid toxicity in DbCM is suggested.
摘要：
糖尿病心肌病（DbCM）的特征是舒张功能障碍，在糖尿病患者中进展为心力衰竭和异常电生理。2型糖尿病患者的血脂异常导致心肌细胞中脂质滴（LD）的积累，并导致脂质毒性，这已被建议驱动DbCM。旨在探索可能促进DbCM中LD降解并恢复心脏功能的潜在途径。证实了LD积累导致DbCM心脏中脂质毒性增加。微脂吞噬途径,而不是传统的大脂吞噬，在DbCM心脏中被激活。RNA-Seq数据和Rab7-CKO小鼠暗示Rab7是微脂吞噬途径的主要调节剂。机械上,Rab7在酪氨酸183处磷酸化，这允许募集Rab相互作用的溶酶体蛋白（Rilp）以进行LDs被溶酶体降解。用Rab7激活剂ML-098处理DbCM小鼠增强了Rilp水平并挽救了观察到的心脏功能障碍。总的来说,建议Rab7-Rilp介导的微脂吞噬可能是治疗DbCM中脂质毒性的有希望的靶标。
