Journal article
Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity
Nature (London), Vol.473(7348), pp.528-531
2011
DOI: 10.1038/nature09968
PMCID: PMC3102791
PMID: 21532591
Abstract
The endoplasmic reticulum (ER) is the main site of protein and lipid synthesis, membrane biogenesis, xenobiotic detoxification and cellular calcium storage, and perturbation of ER homeostasis leads to stress and the activation of the unfolded protein response1. Chronic activation of ER stress has been shown to have an important role in the development of insulin resistance and diabetes in obesity2. However, the mechanisms that lead to chronic ER stress in a metabolic context in general, and in obesity in particular, are not understood. Here we comparatively examined the proteomic and lipidomic landscape of hepatic ER purified from lean and obese mice to explore the mechanisms of chronic ER stress in obesity. We found suppression of protein but stimulation of lipid synthesis in the obese ER without significant alterations in chaperone content. Alterations in ER fatty acid and lipid composition result in the inhibition of sarco/endoplasmic reticulum calcium ATPase (SERCA) activity and ER stress. Correcting the obesity-induced alteration of ER phospholipid composition or hepatic Serca overexpression in vivo both reduced chronic ER stress and improved glucose homeostasis. Hence, we established that abnormal lipid and calcium metabolism are important contributors to hepatic ER stress in obesity.
Details
- Title: Subtitle
- Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity
- Creators
- Suneng Fu - Departments of Genetics and Complex Diseases, and Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, United StatesLing Yang - Departments of Genetics and Complex Diseases, and Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, United StatesPing Li - Departments of Genetics and Complex Diseases, and Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, United StatesOliver HOFMANN - Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, United StatesLee DICKER - Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, United StatesWinston HIDE - Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, United StatesXihong Lin - Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, United StatesSteven M WATKINS - Lipomics Technologies Inc, West Sacramento, California 95691, United StatesAlexander R IVANOV - Departments of Genetics and Complex Diseases, and Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, United StatesGökhan S HOTAMISLIGIL - Departments of Genetics and Complex Diseases, and Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, United States
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.473(7348), pp.528-531
- DOI
- 10.1038/nature09968
- PMID
- 21532591
- PMCID
- PMC3102791
- NLM abbreviation
- Nature
- ISSN
- 0028-0836
- eISSN
- 1476-4687
- Publisher
- Nature Publishing Group; London
- Language
- English
- Date published
- 2011
- Academic Unit
- Molecular Physiology and Biophysics; Anatomy and Cell Biology
- Record Identifier
- 9984025359602771
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