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

American Journal of Physiology. Endocrinology and Metabolism
Shubha Ghosh DastidarDaniel J Conklin

Abstract

Hepatic glutathione S-transferases (GSTs) are dysregulated in human obesity, nonalcoholic fatty liver disease, 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 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 levels, or insulin levels in mice maintained on a normal chow diet; however, compared 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 proteins in the liver. Treatment of GSTP-null mice with the JNK inhibitor 1,9-pyrazoloanthrone (SP600125) significantly attenuated pyruvate-induced hepatic gluconeogenesis and significantly altered correlations between hepatic cytokine mRNAs and metabolic outcomes in GSTP-null mice. Collective...Continue Reading

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Citations

Jun 20, 2020·American Journal of Physiology. Heart and Circulatory Physiology·Amina KunovacJohn M Hollander
May 28, 2021·Frontiers in Nutrition·Amanda E BriesElizabeth M McNeill

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Datasets Mentioned

BETA
GM-103492

Methods Mentioned

BETA
X-ray
PCR
electrophoresis
ELISA

Software Mentioned

ImageQuant TL
R
GraphPad Prism
GraphPad

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