Acetytransferase P300 impairs insulin signaling in obesity

Insulin resistance is the hallmark of obese and type 2 diabetes patients. Defective insulin sensitivity in the liver results in increased glucsoe production, which is the major cause of hyperglycemia in diabetic patients. Increased lipopolysaccharide (LPS) leakage from the gut of diet-induced obesity causes insulin resisitance; moreover, activation of deacetylase Sirtuin1 restore insulin sensitivity in obesity. However, the mechanism resulting in insulin resistance by LPS remains poorly understood. Here, we show that Ep300 (P300) harboring an intrinsic acetyltransferase activity was rapidly induced in the liver of animals fed a high-fat diet, and the induction of Ep300 is through LPS-stimulated activation of ER stress. Induced Ep300 impairs insulin signaling by acetylating mediators in insulin signaling. Inhibition of P300 acetyltransferase activity improves insulin signaling. Thus, Ep300 acetyltransferase activity is a therapeutic target. To determine whether P300 plays an important role in the regulation of glucose and lipid metabolism in the liver of obese mouse models, AAV-shRNAs for scrambled control and P300 functional were injected into mice through the jugular. One week after viral injection, mice were fed on a high-fat diet for another week, then, sacrificed after 6h fasting. Liver tissues were collected, snap-frozen in liquid nitrogen, and stored at 80°C until use. There are 8 samples, 4 samples from control group (shSCR), another 4 samples from treated group (shP300).