Title | p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Duran A, Hernandez ED, Reina-Campos M, Castilla EA, Subramaniam S, Raghunandan S, Roberts LR, Kisseleva T, Karin M, Diaz-Meco MT, Moscat J |
Journal | Cancer Cell |
Volume | 30 |
Issue | 4 |
Pagination | 595-609 |
Date Published | 2016 10 10 |
ISSN | 1878-3686 |
Keywords | Animals, HEK293 Cells, Hepatic Stellate Cells, Humans, Liver Cirrhosis, Liver Neoplasms, Mice, Mice, Knockout, Receptors, Calcitriol, Retinoid X Receptors, Sequestosome-1 Protein, Signal Transduction |
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. |
DOI | 10.1016/j.ccell.2016.09.004 |
Alternate Journal | Cancer Cell |
PubMed ID | 27728806 |
PubMed Central ID | PMC5081228 |
Grant List | R01 DK108743 / DK / NIDDK NIH HHS / United States R01 CA192642 / CA / NCI NIH HHS / United States P01 DK098108 / DK / NIDDK NIH HHS / United States P42 ES010337 / ES / NIEHS NIH HHS / United States R01 CA172025 / CA / NCI NIH HHS / United States P30 CA030199 / CA / NCI NIH HHS / United States R01 DK099205 / DK / NIDDK NIH HHS / United States R01 CA118165 / CA / NCI NIH HHS / United States U01 AA022614 / AA / NIAAA NIH HHS / United States R01 CA163798 / CA / NCI NIH HHS / United States R01 DK101737 / DK / NIDDK NIH HHS / United States |
Related Faculty:
Maria Diaz-Meco Conde, Ph.D.