p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer

Angeles Duran, Eloy D. Hernandez, Miguel Reina-Campos, Elias A. Castilla, Shankar Subramaniam, Sindhu Raghunandan, Lewis R. Roberts, Tatiana Kisseleva, Michael Karin, Maria T. Diaz-Meco, Jorge Moscat

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

Hepatic stellate cells (HSCs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). Vitamin D receptor (VDR) activation in HSCs inhibits liver inflammation and fibrosis. We found that p62/SQSTM1, a protein upregulated in liver parenchymal cells but downregulated in HCC-associated HSCs, negatively controls HSC activation. Total body or HSC-specific p62 ablation potentiates HSCs and enhances inflammation, fibrosis, and HCC progression. p62 directly interacts with VDR and RXR promoting their heterodimerization, which is critical for VDR:RXR target gene recruitment. Loss of p62 in HSCs impairs the repression of fibrosis and inflammation by VDR agonists. This demonstrates that p62 is a negative regulator of liver inflammation and fibrosis through its ability to promote VDR signaling in HSCs, whose activation supports HCC.

Original languageEnglish (US)
Pages (from-to)595-609
Number of pages15
JournalCancer cell
Volume30
Issue number4
DOIs
StatePublished - Oct 10 2016

Keywords

  • fibrosis
  • hepatic stellate cells
  • hepatocellular carcinoma
  • inflammation
  • liver cancer
  • non-alcoholic steatohepatitis
  • nuclear receptors
  • p62
  • sequestosome-1
  • vitamin D receptor

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Duran, A., Hernandez, E. D., Reina-Campos, M., Castilla, E. A., Subramaniam, S., Raghunandan, S., Roberts, L. R., Kisseleva, T., Karin, M., Diaz-Meco, M. T., & Moscat, J. (2016). p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer. Cancer cell, 30(4), 595-609. https://doi.org/10.1016/j.ccell.2016.09.004