Peroxisome Proliferator-activated Receptor α Is Responsible for the Up-regulation of Hepatic Glucose-6-phosphatase Gene Expression in Fasting and db/db Mice

Jin-Sik Bae,Kyung-Sup Kim,Seung-Soon Im,Goo-Taeg Oh,Yong-Ho Ahn,Hail Kim,Mi-Young Kim,Tae-Hyun Kim,Sool-Ki Kwon

doi:10.1074/jbc.m110.157875

Abstract

Glucose-6-phosphatase (G6Pase) is a key enzyme that is responsible for the production of glucose in the liver during fasting or in type 2 diabetes mellitus (T2DM). During fasting or in T2DM, peroxisome proliferator-activated receptor α (PPARα) is activated, which may contribute to increased hepatic glucose output. However, the mechanism by which PPARα up-regulates hepatic G6Pase gene expression in these states is not well understood. We evaluated the mechanism by which PPARα up-regulates hepatic G6Pase gene expression in fasting and T2DM states. In PPARα-null mice, both hepatic G6Pase and phosphoenolpyruvate carboxykinase levels were not increased in the fasting state. Moreover, treatment of primary cultured hepatocytes with Wy14,643 or fenofibrate increased the G6Pase mRNA level. In addition, we have localized and characterized a PPAR-responsive element in the promoter region of the G6Pase gene. Chromatin immunoprecipitation (ChIP) assay revealed that PPARα binding to the putative PPAR-responsive element of the G6Pase promoter was increased in fasted wild-type mice and db/db mice. These results indicate that PPARα is responsible for glucose production through the up-regulation of hepatic G6Pase gene expression during fasting or T2DM animal models.

Highlights

G6Pase (EC 3.1.3.9) is expressed mainly in the liver, kidney, and ␤-cells of the pancreas where the enzyme hydrolyzes glucose 6-phosphate to glucose at the final step of gluconeogenesis [7]
These findings indicate that G6Pase is a direct target of peroxisome proliferator-activated receptors (PPARs)␣ and that PPAR␣ may be responsible for glucose production through the regulation of hepatic G6Pase gene expression during fasting as well as in type 2 diabetes mellitus (T2DM)
MRNA levels of G6Pase and phosphoenolpyruvate carboxykinase (PEPCK) were not increased by fasting in the PPAR␣-null mice, suggesting that PPAR␣ could be involved in the up-regulation of G6Pase and PEPCK gene expression

Summary

Introduction

G6Pase (EC 3.1.3.9) is expressed mainly in the liver, kidney, and ␤-cells of the pancreas where the enzyme hydrolyzes glucose 6-phosphate to glucose at the final step of gluconeogenesis [7]. The synergistic effect of PPAR␣ with glucocorticoid receptor on PEPCK promoter has been studied in liver [30], and several mechanisms accounting for reduced glucose production in PPAR␣-null mice were proposed [23], little is known about direct role of PPAR␣ on the regulation of the gene expression of G6Pase. To explore a molecular mechanism governing the PPAR␣ and gluconeogenic gene expression, mRNA levels of PPAR␣, G6Pase, and PEPCK were measured in the mice subjected to fasting and/or refeeding.

Results

Conclusion