Department of Traditional Chinese Medicine, Shanghai Sixth People's Hospital Affiliated Shanghai Jiaotong University, Shanghai 200233, China.
Diabetes Institute, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Biochem Biophys Res Commun. 2018 Jun 2;500(2):484-489. doi: 10.1016/j.bbrc.2018.04.108. Epub 2018 Apr 21.
Mitochondrial dysfunction is mainly associated with high-fat-diet (HFD)-induced hepatic steatosis. Sennoside A (SA), a commonly used clinical stimulant laxative, is reported to improve energy metabolism and insulin resistance. However, the effect and mechanism of SA on HFD-induced hepatic steatosis remain largely unknown. The aim of this study was to determine the effect and mechanism of SA on HFD-induced hepatic steatosis in mice. We examined the liver and body weight of mice to evaluate the physical changes in the liver. Hematoxylin and eosin (H&E) and oil red O staining were used to detect the lipid accumulation. The mitochondrial structure and function were tested by transmission electron microscopy and the Seahorse XF24 Analyzer. Furthermore, mitochondrial complexes I, II, and IV and voltage-dependent anion channel 1 (VDAC1) protein activity were detected to understand the mechanism of the protective effect on mitochondria. As a result, damage to the structure and function in the hepatic mitochondria of HFD-induced hepatic steatosis was observed in mice. The structural damage was in the form of loss of cristae, mitochondrial swelling, vacuolization and even rupturing of the outer mitochondrial membrane (OMM). Functional alterations were found by activation of complex I and deficiency in complexes II and IV. The VDAC1 activity and the total ATP in the liver tissue was increased under hepatic steatosis conditions. The above effects were reversed by SA. These data suggest that inhibition of VDAC1 may be an underlying mechanism of SA for protecting mitochondria in HFD-induced hepatic steatosis in mice. Thus, VDAC1 may be a promising target for treating fatty liver disease.
线粒体功能障碍主要与高脂肪饮食（HFD）诱导的肝脂肪变性有关。番泻苷 A（SA）是一种常用的临床刺激性泻药，据报道可改善能量代谢和胰岛素抵抗。然而，SA 对 HFD 诱导的肝脂肪变性的作用和机制在很大程度上仍不清楚。本研究旨在确定 SA 对 HFD 诱导的小鼠肝脂肪变性的作用和机制。我们检查了小鼠的肝脏和体重，以评估肝脏的生理变化。苏木精和伊红（H&E）和油红 O 染色用于检测脂质积累。通过透射电子显微镜和 Seahorse XF24 分析仪测试线粒体结构和功能。此外，还检测了线粒体复合物 I、II 和 IV 以及电压依赖性阴离子通道 1（VDAC1）的蛋白活性，以了解对线粒体的保护作用的机制。结果，观察到 HFD 诱导的肝脂肪变性小鼠肝线粒体的结构和功能受损。结构损伤的形式为嵴丢失、线粒体肿胀、空泡化甚至外线粒体膜（OMM）破裂。功能改变表现为复合物 I 的激活和复合物 II 和 IV 的缺乏。在肝脂肪变性条件下，肝组织中的 VDAC1 活性和总 ATP 增加。SA 逆转了上述作用。这些数据表明，抑制 VDAC1 可能是 SA 保护 HFD 诱导的肝脂肪变性小鼠线粒体的潜在机制。因此，VDAC1 可能是治疗脂肪肝疾病的有前途的靶点。
