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. doi: 10.1016/j.ccell.2016.09.004.


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.

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

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • HEK293 Cells
  • Hepatic Stellate Cells / metabolism*
  • Hepatic Stellate Cells / pathology
  • Humans
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Knockout
  • Receptors, Calcitriol / metabolism*
  • Retinoid X Receptors / metabolism
  • Sequestosome-1 Protein / metabolism*
  • Signal Transduction


  • Receptors, Calcitriol
  • Retinoid X Receptors
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • VDR protein, human