Type your tag names separated by a space and hit enter

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 (CB(1)R) promote neural progenitor cell proliferation, and in the liver they promote lipogenesis. These findings suggest the involvement of CB(1)R in the control of liver regeneration. Here we report that mice lacking CB(1)R globally or in hepatocytes only and wild-type mice treated with a CB(1)R antagonist have a delayed proliferative response to two-thirds partial hepatectomy (PHX). In wild-type mice, PHX leads to increased hepatic expression of CB(1)R 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 CB(1)R(-/-) 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 CB(1)R by newly synthesized anandamide promotes liver regeneration by controlling the expression of cell-cycle regulators that drive M phase progression.

Links

  • PMC Free PDF
  • PMC Free Full Text
  • FREE Publisher Full Text
  • Authors+Show Affiliations

    ,

    Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.

    , , , , , , , , , , , , ,

    Source

    MeSH

    Animals
    Arachidonic Acids
    Cell Cycle
    Endocannabinoids
    Forkhead Box Protein M1
    Forkhead Transcription Factors
    Liver
    Liver Regeneration
    Male
    Mice
    Mice, Knockout
    Mitosis
    Phosphatidylinositol 3-Kinases
    Polyunsaturated Alkamides
    Proto-Oncogene Proteins c-akt
    Receptor, Cannabinoid, CB1
    Signal Transduction
    Up-Regulation

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Intramural

    Language

    eng

    PubMed ID

    21383171

    Citation

    Mukhopadhyay, Bani, et al. "Hyperactivation of Anandamide Synthesis and Regulation of Cell-cycle Progression Via Cannabinoid Type 1 (CB1) Receptors in the Regenerating Liver." Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 15, 2011, pp. 6323-8.
    Mukhopadhyay B, Cinar R, Yin S, et al. Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB1) receptors in the regenerating liver. Proc Natl Acad Sci USA. 2011;108(15):6323-8.
    Mukhopadhyay, B., Cinar, R., Yin, S., Liu, J., Tam, J., Godlewski, G., ... Kunos, G. (2011). Hyperactivation of anandamide synthesis and regulation of cell-cycle progression via cannabinoid type 1 (CB1) receptors in the regenerating liver. Proceedings of the National Academy of Sciences of the United States of America, 108(15), pp. 6323-8. doi:10.1073/pnas.1017689108.
    Mukhopadhyay B, et al. Hyperactivation of Anandamide Synthesis and Regulation of Cell-cycle Progression Via Cannabinoid Type 1 (CB1) Receptors in the Regenerating Liver. Proc Natl Acad Sci USA. 2011 Apr 12;108(15):6323-8. PubMed PMID: 21383171.
    * Article titles in AMA citation format should be in sentence-case
    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, Y1 - 2011/03/07/ PY - 2011/3/9/entrez PY - 2011/3/9/pubmed PY - 2011/6/28/medline SP - 6323 EP - 8 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 108 IS - 15 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 (CB(1)R) promote neural progenitor cell proliferation, and in the liver they promote lipogenesis. These findings suggest the involvement of CB(1)R in the control of liver regeneration. Here we report that mice lacking CB(1)R globally or in hepatocytes only and wild-type mice treated with a CB(1)R antagonist have a delayed proliferative response to two-thirds partial hepatectomy (PHX). In wild-type mice, PHX leads to increased hepatic expression of CB(1)R 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 CB(1)R(-/-) 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 CB(1)R by newly synthesized anandamide promotes liver regeneration by controlling the expression of cell-cycle regulators that drive M phase progression. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/21383171/abstract/Hyperactivation_of_anandamide_synthesis_and_regulation_of_cell_cycle_progression_via_cannabinoid_type_1__CB1__receptors_in_the_regenerating_liver_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=21383171 DB - PRIME DP - Unbound Medicine ER -