Sarco(endo)plasmic reticulum Ca 2+ -ATPase 2b is a major regulator of endoplasmic reticulum stress and glucose homeostasis in obesity
- 25 October 2010
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (45), 19320-19325
- https://doi.org/10.1073/pnas.1012044107
Abstract
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.This publication has 19 references indexed in Scilit:
- The regulatory subunits of PI3K, p85α and p85β, interact with XBP-1 and increase its nuclear translocationNature Medicine, 2010
- Hepatic Bax Inhibitor-1 Inhibits IRE1 alpha and Protects from Obesity-associated Insulin Resistance and Glucose IntoleranceJournal of Biological Chemistry, 2010
- GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in miceJCI Insight, 2009
- Endoplasmic Reticulum Stress Plays a Central Role in Development of Leptin ResistanceCell Metabolism, 2009
- Loss of the Tuberous Sclerosis Complex Tumor Suppressors Triggers the Unfolded Protein Response to Regulate Insulin Signaling and ApoptosisMolecular Cell, 2008
- Endoplasmic Reticulum Stress in Disease PathogenesisAnnual review of pathology, 2008
- Signal integration in the endoplasmic reticulum unfolded protein responseNature Reviews Molecular Cell Biology, 2007
- Mechanisms of obesity-associated insulin resistance: many choices on the menuGenes & Development, 2007
- THE MAMMALIAN UNFOLDED PROTEIN RESPONSEAnnual Review of Biochemistry, 2005
- Obesity and insulin resistanceJCI Insight, 2000