AMPKα1 controls hepatocyte proliferation independently of energy balance by regulating Cyclin A2 expression

Abstract

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, AMPKα1, on hepatocyte proliferation.

Methods: Hepatocyte proliferation was determined in AMPKα1 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 AMPKα1 delayed liver regeneration by impacting on G1/S transition phase. The proliferative defect of AMPKα1-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 AMPKα1 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, AMPKα1 controlled cyclin A2 transcription mainly through the ATF/CREB element.

Conclusions: Our study highlights a novel role for AMPKα1 as a positive regulator of hepatocyte division occurring independently of energy balance.

Keywords: AMP-activated protein kinase; AMPK; BrdU; Bromodeoxyuridine; CRE; CaMKK; Calmodulin dependent protein Kinase Kinase; Cyclin A2; EGF; Epidermal Growth Factor; G1/S transition; HGF; Hapatocytes; Hepatocyte Growth Factor; HuR; Human-antigen R; IL-6; Interleukin-6; KO; Knock-Out; LKB1; Liver Kinase B1; Liver regeneration; NOS; Nitric Oxide Synthase; PH; PHH3; PI3K; Partial Hepatectomy; Phosphatidylinositol 3-Kinase; Phospho-Histone H3; ROS; Reactive Oxigen Species; S-Adenosylmethionine; SAMe; STAT; Signal Transducer and Activator of Transcription; WT; Wild Type; cAMP Response Element.