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

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 It has been generally accepted that a surplus of nutrients and energy stimulates synthetic pathways and may lead to client overloading in the ER. However, it has not been demonstrated whether increased de novo protein synthesis and client loading into the ER and/or a diminished productivity of the ER in protein degradation or folding leads to ER stress in obesity. Intriguingly, dephosphorylation of eukaryotic translation initiation factor 2a (eIF2a) in the liver of high-fat-dietfed mice reduced the ER stress response 3 , indicating that additional mechanisms other than translational upregulation may also contribute to ER dysfunction in obesity. To address these mechanistic questions, we first fractionated ER from lean and obese liver tissues (Supplementary We also observed upregulation of protein degradation pathways but did not find a broad change in the quantity of ER chaperones (Supplementar