Hepatic deficiency of Poldip2 in type 2 diabetes dampens lipid and glucose homeostasis.

Abstract

Moderate or low level hydrogen peroxides has been shown to play an important role in vascular smooth muscle cell (VSMC) function, in which the polymerase DNA-directed interacting protein 2 (poldip2), functioned as a key regulator of NOX4 activity. In current study, we unexpectedly found that type 2 diabetes mellitus (T2DM) substantilly suppresses the hepatic poldip2 expression, and that the hepatic deficiency of poldip2 may be correlated with dysregulation of hepatic cholestrol and plasma triglycerides. In cultured hepatocytes, we found that both insulin and leptin may inhibit hepatic expression of poldip2 under high glucose concentration, but these suppressions were totally abolished under normoglycemic condition. POLDIP2 siRNA knockdown significantly impaired the H2O2 induction by insulin or leptin under normoglycemic condition, contributing the accumulation of cholesterol in cultured liver cells. The in vivo restoration of hepatic poldip2 expression in T2DM mice remarkably rescued the moderate H2O2 generation in livers versus control mice, resulting in significant amelioration of hepatic cholesterol accumulation and plasma triglyceride levels. Importantly, the moderate induction of H2O2 in livers dramatically improved the hepatic PI3K-C1/AKT signaling or dampened PI3K-C2γ/AKT signaling through suppression of PTEN and PTP1B activities, thereby inhibiting the hepatic expression of HMGCR and SREBP2 for cholesterol synthesis. Moreover, the restitution of hepatic poldip2 expression in diabetic mice significantly lowered the VLDL-cholesterol production rate, and substantially suppressed PEPCK and G6Pase expressions for gluconeogenesis, thus significantly improving the plasma insulin and glucose levels, and ITT and GTT outcomes in diabetic mice. Our findings suggest that hepatic dysregulation of poldip2 may contribute to diabetic dyslipidemia and hyperglycemia.