Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB₁) receptors in the regenerating liver

Abstract

The mammalian liver regenerates upon tissue loss, which induces quiescent hepatocytes to enter the cell cycle and undergo limited replication under the control of multiple hormones, growth factors, and cytokines. Endocannabinoids acting via cannabinoid type 1 receptors (CB₁R) promote neural progenitor cell proliferation, and in the liver they promote lipogenesis. These findings suggest the involvement of CB₁R in the control of liver regeneration. Here we report that mice lacking CB₁R globally or in hepatocytes only and wild-type mice treated with a CB₁R antagonist have a delayed proliferative response to two-thirds partial hepatectomy (PHX). In wild-type mice, PHX leads to increased hepatic expression of CB₁R and hyperactivation of the biosynthesis of the endocannabinoid anandamide in the liver via an in vivo pathway involving conjugation of arachidonic acid and ethanolamine by fatty-acid amide hydrolase. In wild-type but not CB₁R^−/− mice, PHX induces robust up-regulation of key cell-cycle proteins involved in mitotic progression, including cyclin-dependent kinase 1 (Cdk1), cyclin B2, and their transcriptional regulator forkhead box protein M1 (FoxM1), as revealed by ultrahigh-throughput RNA sequencing and pathway analysis and confirmed by real-time PCR and Western blot analyses. Treatment of wild-type mice with anandamide induces similar changes mediated via activation of the PI3K/Akt pathway. We conclude that activation of hepatic CB₁R by newly synthesized anandamide promotes liver regeneration by controlling the expression of cell-cycle regulators that drive M phase progression.