Mice depleted for Exchange Proteins Directly Activated by cAMP (Epac) exhibit irregular liver regeneration in response to partial hepatectomy

Kathrine Sivertsen Asrud*, Line Pedersen, Reidun Aesoy, Haruna Muwonge, Elise Aasebo, Ina Katrine Nitschke Pettersen, Lars Herfindal, Ross Dobie, Stephen Jenkins, Rolf Kristian Berge, Neil Cowan Henderson, Frode Selheim, Stein Ove Doskeland, Marit Bakke

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The exchange proteins directly activated by cAMP 1 and 2 (Epac1 and Epac2) are expressed in a cell specific manner in the liver, but their biological functions in this tissue are poorly understood. The current study was undertaken to begin to determine the potential roles of Epac1 and Epac2 in liver physiology and disease. Male C57BL/6J mice in which expression of Epac1 and/or Epac2 are deleted, were subjected to partial hepatectomy and the regenerating liver was analyzed with regard to lipid accumulation, cell replication and protein expression. In response to partial hepatectomy, deletion of Epac1 and/or Epac2 led to increased hepatocyte proliferation 36 h post surgery, and the transient steatosis observed in wild type mice was virtually absent in mice lacking both Epac1 and Epac2. The expression of the protein cytochrome P4504a14, which is implicated in hepatic steatosis and fibrosis, was substantially reduced upon deletion of Epac1/2, while a number of factors involved in lipid metabolism were significantly decreased. Moreover, the number of Kupffer cells was affected, and Epac2 expression was increased in the liver of wild type mice in response to partial hepatectomy, further supporting a role for these proteins in liver function. This study establishes hepatic phenotypic abnormalities in mice deleted for Epac1/2 for the first time, and introduces Epac1/2 as regulators of hepatocyte proliferation and lipid accumulation in the regenerative process.

Original languageEnglish
Article number13789
Number of pages17
JournalScientific Reports
Volume9
DOIs
Publication statusPublished - 24 Sep 2019

Keywords

  • HEPATIC STELLATE CELLS
  • HEPATOCYTE PROLIFERATION
  • SUBCELLULAR-LOCALIZATION
  • BINDING PROTEINS
  • EXPRESSION
  • TRANSCRIPTION
  • MURINE
  • MODEL
  • IDENTIFICATION
  • METABOLISM

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