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Author Notes:

P. Kumar,Division of Digestive Disease, Department of Medicine, 615 Michael Street, Room 275, Atlanta, GA 30322,USA. pkuma23@emory.edu

The authors declare they have no conflicts of interest with the contents of this manuscript.

Subjects:

Research Funding:

This work was supported by US Public Health Service Grant RO1 DK062092, DK111678, and DK113147 all to FAA; NIH grant K01DK110264 to RR; and NIH grant F31AA024960 to DMC.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Biophysics
  • Cell Biology
  • Liver fibrosis
  • Adiponectin
  • PTEN
  • DNA methylation
  • microRNA
  • LIVER FIBROSIS
  • EXPRESSION
  • MECHANISM
  • PHOSPHORYLATION
  • PROLIFERATION
  • MICRORNA-29B
  • PHOSPHATASE
  • APOPTOSIS
  • HOMOLOG
  • MIR-21

Adiponectin inhibits hepatic stellate cell activation by targeting the PTEN/AKT pathway

Tools:

Journal Title:

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

Volume:

Volume 1864, Number 10

Publisher:

, Pages 3537-3545

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Adiponectin inhibits hepatic stellate cell (HSC) activation and subsequent development of liver fibrosis via multiple mechanisms. Phosphatase and tensin homolog deletion 10 (PTEN) plays a crucial role in suppression of HSC activation, but its regulation by adiponectin is not fully understood. Here, we investigated the effect of adiponectin on PTEN in LX-2 cells, a human cell line and examined the underlying molecular mechanisms involved in adiponectin-mediated upregulation of PTEN activity during fibrosis. PTEN expression was found to be significantly reduced in the livers of mice treated with CCl 4 , whereas its expression was rescued by adiponectin treatment. The DNA methylation proteins DNMT1, DNMT3A, and DNMT3B are all highly expressed in activated primary HSCs compared to quiescent HSCs, and thus represent additional regulatory targets during liver fibrogenesis. Expression of DNMT proteins was significantly induced in the presence of fibrotic stimuli; however, only DNMT3B expression was reduced in the presence of adiponectin. Adiponectin-induced suppression of DNMT3B was found to be mediated by enhanced miR-29b expression. Furthermore, PTEN expression was significantly increased by overexpression of miR-29b, whereas its expression was markedly reduced by a miR-29b inhibitor in LX-2 cells. These findings suggest that adiponectin-induced upregulation of miR-29b can suppress DNMT3B transcription in LX-2 cells, thus resulting in reduced methylation of PTEN CpG islands and ultimately suppressing the PI3K/AKT pathway. Together, these data suggest a possible new explanation for the inhibitory effect of adiponectin on HSC activation and liver fibrogenesis.

Copyright information:

© 2018 Elsevier B.V.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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