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Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity

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.

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Figure 1: Proteomic and lipidomic landscape of the lean and obese ER.
Figure 2: An increased PC/PE ratio impairs SERCA activity and ER homeostasis.
Figure 3: Suppression of liver Pemt expression corrects the ER PC/PE ratio, relieves ER stress and improves systemic glucose homeostasis in obesity.
Figure 4: Exogenous Serca expression alleviates ER stress and improves systemic glucose homeostasis.

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Acknowledgements

We thank A. Porter, E. Freeman and R. Davis for technical assistance. The anti-HERP antibody is a gift of Y. Hirabayashi. We thank the members of the G.S.H. laboratory for scientific discussions and critical reading of the manuscript. This work was supported in part by the National Institutes of Health (DK52539 and 1RC4-DK090942) and a research grant from Syndexa Pharmaceuticals to G.S.H. S.F. was supported in part by the NIH/NIEHS postdoctoral training grant (T32ES007155).

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S.F. designed, performed experiments, analysed and interpreted the results and wrote the manuscript; L.Y. and P.L. performed some animal experiments; O.H., L.D., W.H. and X.L. performed statistical and bioinformatic analysis of the proteomic data; S.W.M quantified the lipid composition of ER and analysed the data; A.R.I. analysed the protein composition of ER; G.S.H. generated the hypothesis, designed the project, analysed and interpreted the data and wrote the manuscript.

Corresponding author

Correspondence to Gökhan S. Hotamisligil.

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Competing interests

G.S.H. is a shareholder of Syndexa Pharmaceuticals and serves on the Scientific Advisory Board. A patent application has been filed using technologies discussed in this paper.

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Fu, S., Yang, L., Li, P. et al. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473, 528–531 (2011). https://doi.org/10.1038/nature09968

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