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

By Suneng Fu, Ling Yang, Ping Li, Oliver Hofmann, Lee H. Dicker, Winston A Hide, Xihong Lin, S. Watkins, Alexander Ivanov, G. Hotamışlıgil. Nature, 2011

994 citations recorded by the source corpus.

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 response. Chronic activation of ER stress has been shown to have an important role in the development of insulin resistance and diabetes in obesity. 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.

Subfields: Cell Biology, Epidemiology, Surgery

View Paper: https://www.semanticscholar.org/paper/0a3046204cfe4213ee75a2ed792188e86dff2c64

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cell Biology

1. C. Hetz
2. G. Hotamışlıgil
3. É. Chevet
4. D. Ron
5. R. Kaufman
6. Laurie H. Glimcher
7. F. Papa
8. J. Cubillos-Ruiz

In Epidemiology

1. C. Hetz
2. G. Hotamışlıgil
3. É. Chevet
4. Ali Canbay
5. M. Trauner
6. G. Gerken
7. Rebekka A. Hannivoort
8. L. Bechmann

In Surgery

1. C. Hetz
2. G. Hotamışlıgil
3. É. Chevet
4. Doralicia Casares
5. D. Ron
6. C. A. Rosselló
7. P. Escribá
8. R. Kaufman

Citations in the corpus

• Membrane Lipid Composition: Effect on Membrane and Organelle Structure, Function and Compartmentalization and Therapeutic Avenues (2019, background): “In parallel, an elevated degree of membrane saturation disrupts calcium homeostasis and triggers liver ER stress [164].”
• The unfolded protein response: controlling cell fate decisions under ER stress and beyond (2012, positive): “Through a proteomic and lipidomic approach, one group found drastic alterations in the lipid ER content of cells in the livers of obese mic”
• Insulin receptor signaling in normal and insulin-resistant states. (2014, background): “Moreover, an increase in the phosphatidylcholine (PC) to phosphatidylethanolamine (PE) ratio in endoplasmic reticulum leads to the activation of ER stress and is associated with insulin resistance (Fu et al. 2011).”
• Triglyceride metabolism in the liver (2017, neutral): “In this model, decreased ER Ca2+ content impairs intraluminal Ca2+-dependent chaperones function and is a cause for ER stress (91).”
• Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains (2013, background): “In mammals, altered membrane lipid composition leads to ER calcium depletion (11, 14).”
• Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease. (2018, background): “Accumulation of phosphatidylcholine leads to the inhibition of SERCA activity and reduction of ER [Ca], which induces ER stress as the majority of ER chaperones are Ca-dependent(91).”
• Role of Oxidative Stress in Pathophysiology of Nonalcoholic Fatty Liver Disease (2018, background): “The expression of SERCA was shown to be reduced in animal models of obesity and diabetes, and its inhibition was associated with the activation of ER stress response, resulting in UPR-mediated apoptotic pathways [58].”
• The interaction of hepatic lipid and glucose metabolism in liver diseases. (2012, background): “Interestingly, lipid accumulation and altered composition of phospholipids within ER membranes further promotes ER stress and IR in obese mice [8].”