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

Bani Mukhopadhyay, Resat Cinar, Shi Yin, Jie Liu, Joseph Tam, Grzegorz Godlewski, Judith Harvey-White, Isioma Mordi, Benjamin F. Cravatt, Sophie Lotersztajn, Bin Gao, Qiaoping Yuan, Kornel Schuebel, David Goldman, George Kunos

Research output: Contribution to journalArticlepeer-review

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 upregulation 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.

Original languageEnglish (US)
Pages (from-to)6323-6328
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number15
DOIs
StatePublished - Apr 12 2011
Externally publishedYes

ASJC Scopus subject areas

  • General

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