TY - JOUR
T1 - Hyperactivation of anandamide synthesis and regulation of cell-Cycle progression via cannabinoid type 1 (CB1) receptors in the regenerating liver
AU - Mukhopadhyay, Bani
AU - Cinar, Resat
AU - Yin, Shi
AU - Liu, Jie
AU - Tam, Joseph
AU - Godlewski, Grzegorz
AU - Harvey-White, Judith
AU - Mordi, Isioma
AU - Cravatt, Benjamin F.
AU - Lotersztajn, Sophie
AU - Gao, Bin
AU - Yuan, Qiaoping
AU - Schuebel, Kornel
AU - Goldman, David
AU - Kunos, George
PY - 2011/4/12
Y1 - 2011/4/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79955041521&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79955041521&partnerID=8YFLogxK
U2 - 10.1073/pnas.1017689108
DO - 10.1073/pnas.1017689108
M3 - Article
C2 - 21383171
AN - SCOPUS:79955041521
SN - 0027-8424
VL - 108
SP - 6323
EP - 6328
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 15
ER -