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 Rowland Roberts, Tatiana Kisseleva, Michael Karin, Maria T. Diaz-Meco, Jorge Moscat

Research output: Contribution to journalArticle

56 Citations (Scopus)

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

Fingerprint

Hepatic Stellate Cells
Calcitriol Receptors
Liver Neoplasms
Fibrosis
Hepatocellular Carcinoma
Liver Cirrhosis
Inflammation
Down-Regulation
Liver

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

Cite this

Duran, A., Hernandez, E. D., Reina-Campos, M., Castilla, E. A., Subramaniam, S., Raghunandan, S., ... 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

p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer. / Duran, Angeles; Hernandez, Eloy D.; Reina-Campos, Miguel; Castilla, Elias A.; Subramaniam, Shankar; Raghunandan, Sindhu; Roberts, Lewis Rowland; Kisseleva, Tatiana; Karin, Michael; Diaz-Meco, Maria T.; Moscat, Jorge.

In: Cancer Cell, Vol. 30, No. 4, 10.10.2016, p. 595-609.

Research output: Contribution to journalArticle

Duran, A, Hernandez, ED, Reina-Campos, M, Castilla, EA, Subramaniam, S, Raghunandan, S, Roberts, LR, Kisseleva, T, Karin, M, Diaz-Meco, MT & Moscat, J 2016, 'p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer', Cancer Cell, vol. 30, no. 4, pp. 595-609. https://doi.org/10.1016/j.ccell.2016.09.004
Duran A, Hernandez ED, Reina-Campos M, Castilla EA, Subramaniam S, Raghunandan S et al. p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer. Cancer Cell. 2016 Oct 10;30(4):595-609. https://doi.org/10.1016/j.ccell.2016.09.004
Duran, Angeles ; Hernandez, Eloy D. ; Reina-Campos, Miguel ; Castilla, Elias A. ; Subramaniam, Shankar ; Raghunandan, Sindhu ; Roberts, Lewis Rowland ; Kisseleva, Tatiana ; Karin, Michael ; Diaz-Meco, Maria T. ; Moscat, Jorge. / p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer. In: Cancer Cell. 2016 ; Vol. 30, No. 4. pp. 595-609.
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