EP 4 receptor-associated protein regulates gluconeogenesis in the liver and is associated with hyperglycemia in diabetic mice

Am J Physiol Endocrinol Metab. 2019 Mar 1;316(3):E410-E417. doi: 10.1152/ajpendo.00035.2018. Epub 2018 Dec 18.


Prostaglandin E2 receptor 4-associated protein (EPRAP) is a key molecule in suppressing inflammatory responses in macrophages. EPRAP is expressed not only in macrophages but also in hepatocytes; however, the role of EPRAP in hepatocytes has not yet been defined. To examine the physiological role of hepatic EPRAP in mice, we performed the glucose tolerance test and the hyperinsulinemic-euglycemic clamp in high-fat sucrose diet (HFSD)-fed wild-type (WT) and Eprap null mice. We evaluated the contribution of EPRAP to gluconeogenesis by pyruvate tolerance test and primary hepatocyte experiments. Furthermore, lentivirus-expressing Eprap-specific small-hairpin RNA was injected in db/ db mice. HFSD-fed Eprap null mice had significantly lower blood glucose levels than HFSD-fed WT mice. Eprap null mice also had low glucose levels after fasting or pyruvic acid injection. Moreover, primary hepatocytes from Eprap-deficient mice showed decreased glucose production and lower expression of the Phosphoenol pyruvate carboxykinase and Glucose 6-phosphatase genes. Lentivirus-mediated hepatic Eprap suppression decreased glucose levels and the expression of gluconeogenic genes in db/ db mice. We conclude that EPRAP regulates gluconeogenesis in hepatocytes and is associated with hyperglycemia in diabetic mice. Our data suggest that suppression of EPRAP could be a novel strategy for the treatment of diabetes.

Keywords: EPRAP; diabetes; gluconeogenesis; hyperglycemia; insulin sensitivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics*
  • Diet, High-Fat
  • Dietary Sucrose
  • Gene Expression Regulation*
  • Gluconeogenesis / genetics*
  • Glucose Clamp Technique
  • Glucose-6-Phosphatase / genetics
  • Hepatocytes / metabolism*
  • Hyperglycemia / genetics*
  • Liver / metabolism*
  • Mice
  • Mice, Knockout
  • Phosphoenolpyruvate Carboxykinase (GTP) / genetics


  • Cell Cycle Proteins
  • Dietary Sucrose
  • EPRAP protein, mouse
  • Glucose-6-Phosphatase
  • Phosphoenolpyruvate Carboxykinase (GTP)