p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer.
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.
Mesh Terms:
Animals, HEK293 Cells, Hepatic Stellate Cells, Humans, Liver Cirrhosis, Liver Neoplasms, Mice, Mice, Knockout, Receptors, Calcitriol, Retinoid X Receptors, Sequestosome-1 Protein, Signal Transduction
Animals, HEK293 Cells, Hepatic Stellate Cells, Humans, Liver Cirrhosis, Liver Neoplasms, Mice, Mice, Knockout, Receptors, Calcitriol, Retinoid X Receptors, Sequestosome-1 Protein, Signal Transduction
Cancer Cell
Date: Dec. 10, 2015
PubMed ID: 27728806
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