Sarco(endo)plasmic reticulum Ca²⁺-ATPase 2b is a major regulator of endoplasmic reticulum stress and glucose homeostasis in obesity

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 Ca²⁺ is imperative for maintenan...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2010-11, Vol.107 (45), p.19320-19325
Main Authors: Park, Sang Won, Zhou, Yingjiang, Lee, Jaemin, Lee, Justin, Ozcan, Umut, Karin, Michael
Format: Article
Language:English
Subjects:
Adenoviruses
Animals
Biological Sciences
Blood
Blood Glucose - metabolism
Ca super(2+)-transporting ATPase
Calcium
Diabetes mellitus
Diabetes Mellitus - metabolism
Drug development
Endoplasmic reticulum
Endoplasmic Reticulum - metabolism
Fatty Liver
Gene expression
Glucose Intolerance
Glucose tolerance
Homeostasis
Insulin
Lipid Metabolism
Lipids
Liver
Liver - metabolism
Messenger RNA
Mice
Obesity
Obesity - metabolism
Refeeding
Sarcoplasmic Reticulum Calcium-Transporting ATPases - physiology
Stress
Stress, Physiological
Triglycerides
Type 2 diabetes mellitus
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Summary: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 Ca²⁺ is imperative for maintenance of normal ER function and this high Ca²⁺ concentration of ER is maintained by sarco(endo)plasmic reticulum Ca²⁺-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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1012044107