Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2010 Nov 9;107(45):19320-5. doi: 10.1073/pnas.1012044107. Epub 2010 Oct 25.
Increased endoplasmic reticulum (ER) stress is one of the central mechanisms that lead to dysregulated metabolic homeostasis in obesity. It is thus crucial to understand the underpinnings of the mechanisms that lead to the development of ER stress. A high level of ER Ca(2+) is imperative for maintenance of normal ER function and this high Ca(2+) concentration of ER is maintained by sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA). Here, we show that SERCA2b protein and mRNA levels are dramatically reduced in the liver of obese mice and restoration of SERCA2b in the liver of obese and diabetic mice alleviates ER stress, increases glucose tolerance, and significantly reduces the blood glucose levels. Furthermore, overexpression of SERCA2b in the liver of obese mice significantly reduces the lipogenic gene expression and the triglyceride content in the liver. Our results document the importance of SERCA2b in dysregulated glucose and lipid homeostasis in the liver of obese mice and suggest development of drugs to increase SERCA2b activity for treatment of type 2 diabetes and nonalcoholic steatohepatitis.
内质网（ER）应激的增加是导致肥胖症代谢稳态失调的核心机制之一。因此，了解导致 ER 应激发展的机制基础至关重要。内质网中钙离子（Ca(2+)）的高水平对于维持正常的 ER 功能是必要的，而内质网中这种高浓度的 Ca(2+)则是由肌浆（内质）网 Ca(2+)-ATP 酶（SERCA）维持的。在这里，我们发现在肥胖小鼠的肝脏中，SERCA2b 蛋白和 mRNA 水平显著降低，并且在肥胖和糖尿病小鼠的肝脏中恢复 SERCA2b 可以减轻 ER 应激、增加葡萄糖耐量，并显著降低血糖水平。此外，在肥胖小鼠的肝脏中过表达 SERCA2b 可显著降低肝脏中脂肪生成基因的表达和甘油三酯含量。我们的研究结果证明了 SERCA2b 在肥胖小鼠肝脏中葡萄糖和脂质稳态失调中的重要性，并提示开发增加 SERCA2b 活性的药物用于治疗 2 型糖尿病和非酒精性脂肪性肝炎。
