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 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.
Park
Sang Won
SW
Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Zhou
Yingjiang
Y
Lee
Jaemin
J
Lee
Justin
J
Ozcan
Umut
U
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005234:Fatty Liver; D018149:Glucose Intolerance; D006706:Homeostasis; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D009765:Obesity / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000502:physiology*; D013312:Stress, Physiological
D001786:Blood Glucose; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse