ER is the main site of protein and lipid synthesis and calcium storage. Disrupting ER homeostasis can lead to ER stress and activation of the unfolded protein response. Obesity causes chronic ER stress, and this is known to have an important role in the development of insulin resistance and diabetes. However, the mechanisms behind ER stress in this setting are not well established. “There are two opposing, but not necessarily exclusive, hypotheses in the field: protein overloading and lipotoxicity,” explains Fu. “The protein-overloading hypothesis suggests there may be increased protein synthesis in obesity, which could overwhelm the chaperone system in the ER. The lipotoxicity hypothesis proposes lipid-induced damage to the integrity of the ER.”
The researchers assessed the protein and lipid composition of hepatic ER purified from lean and obese mice. To their surprise, the researchers found that protein synthesis was generally supressed, whereas de novo lipogenesis seeemed to be enhanced in ER from obese tissue. “This in turn resulted in specific compositional changes in ER phospholipids,” says Fu. In particular, obese ER was found to have a high ratio of phosphatidycholine (PC) to phosphatidyethanolamine (PE). This altered PC:PE ratio was shown to inhibit the calcium transport activity of sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA). As calcium has an important role in mediating protein folding in the ER, disrupting calcium homeostasis could contribute to ER stress. Indeed, Fu and colleagues demonstrated that correcting the PC:PE ratio or SERCA function led to a reduction in chronic ER stress.
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