TY - JOUR
T1 - Mice depleted for Exchange Proteins Directly Activated by cAMP (Epac) exhibit irregular liver regeneration in response to partial hepatectomy
AU - Asrud, Kathrine Sivertsen
AU - Pedersen, Line
AU - Aesoy, Reidun
AU - Muwonge, Haruna
AU - Aasebo, Elise
AU - Pettersen, Ina Katrine Nitschke
AU - Herfindal, Lars
AU - Dobie, Ross
AU - Jenkins, Stephen
AU - Berge, Rolf Kristian
AU - Henderson, Neil Cowan
AU - Selheim, Frode
AU - Doskeland, Stein Ove
AU - Bakke, Marit
PY - 2019/9/24
Y1 - 2019/9/24
N2 - 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.
AB - 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.
KW - HEPATIC STELLATE CELLS
KW - HEPATOCYTE PROLIFERATION
KW - SUBCELLULAR-LOCALIZATION
KW - BINDING PROTEINS
KW - EXPRESSION
KW - TRANSCRIPTION
KW - MURINE
KW - MODEL
KW - IDENTIFICATION
KW - METABOLISM
U2 - 10.1038/s41598-019-50219-8
DO - 10.1038/s41598-019-50219-8
M3 - Article
SN - 2045-2322
VL - 9
JO - Scientific Reports
JF - Scientific Reports
M1 - 13789
ER -