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

Lipid metabolism in obesity The function of the endoplasmic reticulum (ER) changes during obesity: in the liver, ER-associated protein synthesis slows down, and genes involved in lipid metabolism are switched on. ER stress is an important factor in obesity, insulin resistance and type 2 diabetes. A possible mechanism for this link has now been identified. Perturbation of fatty acid and lipid metabolism in the ER inhibits the activity of SERCA, the main ER calcium importer. Changing the lipid composition or increasing the amount of SERCA in the ER is shown to relieve the stress and improve glucose homeostasis in vivo . 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 1 . Chronic activation of ER stress has been shown to have an important role in the development of insulin resistance and diabetes in obesity 2 . 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.