Glutathione S-transferase P deficiency induces glucose intolerance via JNK-dependent enhancement of hepatic gluconeogenesis
| Autor: | Daniel J. Conklin, Shubha Ghosh Dastidar, Ganapathy Jagatheesan, Aruni Bhatnagar, Bradford G. Hill, Petra Haberzettl, Jasmit Shah |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Hepatic gluconeogenesis Physiology Endocrinology Diabetes and Metabolism Inflammation Type 2 diabetes 03 medical and health sciences Mice 0302 clinical medicine Physiology (medical) Internal medicine Diabetes mellitus Nonalcoholic fatty liver disease Glucose Intolerance medicine Animals Glutathione Transferase Anthracenes Mice Knockout business.industry Gluconeogenesis JNK Mitogen-Activated Protein Kinases medicine.disease Obesity 030104 developmental biology Endocrinology Liver 030220 oncology & carcinogenesis Glutathione S-Transferase P Body Composition medicine.symptom business Research Article |
| Popis: | 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. Collectively, these findings suggest that hepatic GSTP plays a pivotal role in glucose handling by regulating JNK-dependent control of hepatic gluconeogenesis. Thus, hepatic GSTP-JNK dysregulation may be a target of new therapeutic interventions during early stages of glucose intolerance to prevent the worsening metabolic derangements associated with human obesity and its relentless progression to diabetes. |
| Databáze: | OpenAIRE |
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