Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, 410 N, 12th St., Richmond, VA 23298, USA.
J Pharmacol Exp Ther. 2010 Sep 1;334(3):839-46. doi: 10.1124/jpet.110.168815. Epub 2010 Jun 11.
The present study tested a hypothesis that excess accumulation of sphingolipid, ceramide, its metabolites, or a combination contributes to the development of obesity and associated kidney damage. Liquid chromatography/mass spectrometry analysis demonstrated that C57BL/6J mice on the high-fat diet (HFD) had significantly increased plasma total ceramide levels compared with animals fed a low-fat diet (LFD). Treatment of mice with the acid sphingomyelinase (ASMase) inhibitor amitriptyline significantly attenuated the HFD-induced plasma ceramide levels. Corresponding to increase in plasma ceramide, the HFD significantly increased the body weight gain, plasma leptin concentration, urinary total protein and albumin excretion, glomerular damage index, and adipose tissue ASMase activity compared with the LFD-fed mice. These HFD-induced changes were also significantly attenuated by treatment of mice with amitriptyline. In addition, the decline of plasma glucose concentration after an intraperitoneal injection of insulin (0.15 U/kg b.wt.) was more sustained in mice on the HFD with amitriptyline than on the HFD alone. Intraperitoneal injection of glucose (3 g/kg b.wt.) resulted in a slow increase followed by a rapid decrease in the plasma glucose concentration in LFD and HFD plus amitriptyline-treated mice, but such blood glucose response was not observed in HFD-fed mice. Immunofluorescence analysis demonstrated a decrease in the podocin and an increase in the desmin in the glomeruli of HFD-fed mice compared with the LFD and HFD plus amitriptyline-treated mice. In conclusion, our results reveal a pivotal role for ceramide biosynthesis in obesity, metabolic syndrome, and associated kidney damage.
本研究检验了一个假设，即鞘脂、神经酰胺及其代谢物的过度积累，或者它们的组合，导致肥胖和相关的肾脏损伤的发生。液相色谱/质谱分析表明，高脂肪饮食（HFD）喂养的 C57BL/6J 小鼠与低脂饮食（LFD）喂养的动物相比，血浆总神经酰胺水平显著升高。用酸性鞘磷脂酶（ASMase）抑制剂阿米替林处理小鼠，显著降低了 HFD 诱导的血浆神经酰胺水平。与血浆神经酰胺增加相对应，HFD 显著增加了体重增加、血浆瘦素浓度、尿总蛋白和白蛋白排泄、肾小球损伤指数和脂肪组织 ASMase 活性，与 LFD 喂养的小鼠相比。用阿米替林处理小鼠也显著减轻了这些 HFD 诱导的变化。此外，与单独给予 HFD 的小鼠相比，给予 HFD 加阿米替林的小鼠的胰岛素（0.15 U/kg b.wt.）腹腔注射后血糖浓度的下降更为持续。腹腔内注射葡萄糖（3 g/kg b.wt.）后，LFD 和 HFD 加阿米替林处理的小鼠的血糖浓度缓慢增加，然后迅速下降，但在给予 HFD 的小鼠中未观察到这种血糖反应。免疫荧光分析表明，与 LFD 和 HFD 加阿米替林处理的小鼠相比，HFD 喂养的小鼠肾小球中的足细胞减少，结蛋白增加。总之，我们的结果揭示了神经酰胺生物合成在肥胖、代谢综合征和相关的肾脏损伤中的关键作用。
