Glutathione S-transferase P deficiency induces glucose intolerance via JNK-dependent enhancement of hepatic gluconeogenesis

Hepatic glutathione S-transferases (GSTs) are dysregulated in human obesity, non-alcoholic fatty liver disease (NAFLD) and diabetes. The multifunctional GST Pi isoform (GSTP) catalyzes the conjugation of glutathione with acrolein and inhibits c-Jun NH2-terminal kinase (JNK) activation. Herein, we tested whether GSTP deficiency disturbs glucose homeostasis in mice. Hepatic GST proteins were downregulated by short-term high-fat diet (HFD) in wild type (WT) mice concomitant with increased glucose intolerance, JNK activation, and cytokine mRNAs in the liver. Genetic deletion of GSTP did not affect body composition, fasting blood glucose or insulin levels in mice maintained on a normal chow (NC) diet; however, in comparison with WT mice, the GSTP-Null mice were glucose intolerant. In GSTP-Null mice, pyruvate intolerance, reflecting increased hepatic gluconeogenesis, was accompanied by elevated levels of activated JNK, cytokine mRNAs and glucose-6-phosphatase (G6P) proteins in the liver. Treatment of GSTP-Null ...