Statins therapy is efficacious in diminishing the risk of major cardiovascular events in diabetic patients. However, our research has uncovered a correlation between the prolonged administration of statins and an elevated risk of myocardial dysfunction in patients with type II diabetes mellitus (TIIDM). Here, we report the induction of sterol regulatory element-binding protein 1 (SREBP1) activation, associated lipid peroxidation, and the consequent diabetic myocardial dysfunction after statin treatment and explored the underlying mechanisms. In db/db mice, we observed that 40 weeks atorvastatin (5 and 10 mg/kg) and rosuvastatin (20 mg/kg) administration exacerbated diabetic myocardial dysfunction by echocardiography and cardiomyocyte contractility assay, increased myocardial inflammation and fibrosis as shown by CD68, IL-1β, Masson's staining and Collagen1A1 immunohistochemistry (IHC) staining, increased respiratory exchange ratio (RER) by metabolic cage system assessment, exacerbated mitochondrial structural pathological changes by transmission electron microscopy (TEM) examination, increased deposition of lipid and glycogen by TEM, Oil-red and periodic acid-schiff stain (PAS) staining, which were corresponded with augmented levels of myocardial SREBP1 protein and lipid peroxidation marked by 4-hydroxynonenal (4-HNE) staining. Comparable myocardial fibrosis was also observed in KK-ay and low-dose streptozotocin (STZ)-induced TIIDM mice. Elevated SREBP1 levels were observed in the heart tissues from diabetic patients, which was positively correlated with their myocardial dysfunction. To elucidate the role of statin induced SREBP1 in lipid peroxidation and lipid deposition and related mechanism, we cultured neonatal mouse primary cardiomyocytes (NMPCs) and treated them with atorvastatin (10 μM, 24 h), tracing with [U–13C]-glucose and evaluating for SREBP1 expression and localization. We found that statin treatment elevated de novo lipogenesis (DNL) and the levels of SREBP1 cleavage-activating protein (SCAP), reduced the interaction of SCAP with insulin-induced gene 1 (Insig1), and enhance SCAP/SREBP1 translocation to the Golgi, which facilitate SREBP1 cleavage leading to its nuclear trans-localization and activation in NMPCs. Ultimately, SREBP1 knockdown or l-carnitine mitigated long-term statins therapy induced lipid peroxidation and myocardial fibrosis in low-dose STZ treated SREBP1+/− mice and l-carnitine treated db/db mice. In conclusion, we demonstrated that statin therapy may augment DNL by activating SREBP1, resulting in myocardial lipid peroxidation and lipid deposition.

中文翻译：

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SREBP1 诱导介导 TIIDM 小鼠长期他汀类药物治疗相关的心肌脂质过氧化和脂质沉积


他汀类药物治疗可有效降低糖尿病患者发生主要心血管事件的风险。然而，我们的研究揭示了他汀类药物的长期给药与 II 型糖尿病患者 （TIIDM） 心肌功能障碍风险升高之间的相关性。在这里，我们报道了他汀类药物治疗后甾醇调节元件结合蛋白 1 （SREBP1） 激活的诱导、相关的脂质过氧化以及随之而来的糖尿病心肌功能障碍，并探讨了潜在的机制。在 db/db 小鼠中，我们观察到 40 周阿托伐他汀（5 和 10 mg/kg）和瑞舒伐他汀（20 mg/kg）给药通过超声心动图和心肌细胞收缩性测定加剧了糖尿病心肌功能障碍，心肌炎症和纤维化增加，如 CD68、IL-1β、Masson 染色和胶原蛋白 1A1 免疫组织化学 （IHC） 染色所示，代谢笼系统评估呼吸交换比 （RER） 增加， 透射电子显微镜 （TEM） 检查加剧了线粒体结构病理变化，TEM 增加了脂质和糖原沉积，油红和高碘酸希夫染色 （PAS） 染色，对应于心肌 SREBP1 蛋白水平升高和 4-羟基壬烯醛 （4-HNE） 染色标志的脂质过氧化。在 KK-ay 和低剂量链脲佐菌素 （STZ） 诱导的 TIIDM 小鼠中也观察到类似的心肌纤维化。在糖尿病患者的心脏组织中观察到 SREBP1 水平升高，这与他们的心肌功能障碍呈正相关。 为了阐明他汀类药物诱导的 SREBP1 在脂质过氧化和脂质沉积中的作用及相关机制，我们培养了新生小鼠原代心肌细胞 （NMPCs） 并用阿托伐他汀 （10 μM，24 h） 处理它们，用 [U-13C]-葡萄糖示踪并评估 SREBP1 的表达和定位。我们发现他汀类药物治疗提高了从头脂肪生成 （DNL） 和 SREBP1 裂解激活蛋白 （SCAP） 的水平，减少了 SCAP 与胰岛素诱导的基因 1 （Insig1） 的相互作用，并增强了 SCAP/SREBP1 向高尔基体的易位，从而促进了 SREBP1 的切割，导致其在 NMPC 中的核转定位和激活。最终，SREBP1 敲低或 l-肉碱减轻了低剂量 STZ 中长期他汀类药物治疗诱导的脂质过氧化和心肌纤维化处理的 SREBP1 + / - 小鼠和 L-肉碱处理的 DB/dB 小鼠。总之，我们证明他汀类药物治疗可能通过激活 SREBP1 来增强 DNL，导致心肌脂质过氧化和脂质沉积。