AMPK alpha 1 controls hepatocyte proliferation independently of energy balance by regulating Cyclin A2 expression

作者：Merlen Gregory; Gentric Geraldine; Celton Morizur Severine; Foretz Marc; Guidotti Jacques Emmanuel; Fauveau Veronique; Leclerc Jocelyne; Viollet Benoit; Desdouets Chantal^*

来源：Journal of Hepatology, 2014, 60(1): 152-159.

DOI：10.1016/j.jhep.2013.08.025

• AMPK
• Liver regeneration
• Hapatocytes
• G1/S transition
• Cyclin A2

Background: AMP-activated protein kinase (AMPK) is an evolutionarily conserved sensor of cellular energy status that contributes to restoration of energy homeostasis by slowing down ATP-consuming pathways and activating ATP-producing pathways. Unexpectedly, in different systems, AMPK is also required for proper cell division. In the current study, we evaluated the potential effect of the AMPK catalytic subunit, AMPK alpha 1, on hepatocyte proliferation.
Methods: Hepatocyte proliferation was determined in AMPK alpha 1 knockout and wild-type mice in vivo after two thirds partial hepatectomy, and in vitro in primary hepatocyte cultures. The activities of metabolic and cell cycle-related signaling pathways were measured.
Results: After partial hepatectomy, hepatocytes proliferated rapidly, correlating with increased AMPK phosphorylation. Deletion of AMPK alpha 1 delayed liver regeneration by impacting on G1/S transition phase. The proliferative defect of AMPK alpha 1-deficient hepatocytes was cell autonomous, and independent of energy balance. The priming phase, lipid droplet accumulation, protein anabolic responses and growth factor activation after partial hepatectomy occurred normally in the absence of AMPK alpha 1 activity. By contrast, mRNA and protein expression of cyclin A2, a key driver of S phase progression, were compromised in the absence of AMPK activity. Importantly, AMPK alpha 1 controlled cyclin A2 transcription mainly through the ATF/CREB element.
Conclusions: Our study highlights a novel role for AMPK alpha 1 as a positive regulator of hepatocyte division occurring independently of energy balance.

• 出版日期2014-1