Cystatin C attenuates insulin signaling transduction by promoting endoplasmic reticulum stress in hepatocytes

It has been reported that cystatin c (Cys C) closely correlates with metabolic disorders such as obesity and diabetes. However, it is still unknown whether Cys C plays a role for these disorders. Our results showed that the insulin signal transduction was largely impaired by Cys C in hepatocytes. In myotubes, however, the insulin signal transduction was not affected. Following experiments revealed that Cys C could induce endoplasmic reticulum stress (ER stress) in hepatocytes, whereas Cys C had no such an effect in myotubes. The alleviation of ER stress by 4-Phenyl butyric acid (4-PBA) restored the impaired insulin signal transduction in Cys C-treated hepatocytes. These results provided direct evidence that, by inducing ER stress, Cys C impairs insulin signal transduction in hepatocytes.