title: p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer.
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.
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Angeles
authors.initials: A
authors.lastname: Duran
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Eloy D
authors.initials: ED
authors.lastname: Hernandez
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.|Sanford Burnham Prebys Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Reina-Campos
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Elias A
authors.initials: EA
authors.lastname: Castilla
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Shankar
authors.initials: S
authors.lastname: Subramaniam
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Sindhu
authors.initials: S
authors.lastname: Raghunandan
authors.affiliation: Department of Bioengineering, Department of Cellular and Molecular Medicine, and Department of Chemistry and Biochemistry, Departments of Pharmacology and Pathology, Moores Cancer Center, UCSD School of Medicine, La Jolla, CA 92093-0723, USA.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
authors.affiliation: Department of Surgery, Departments of Pharmacology and Pathology, Moores Cancer Center, UCSD School of Medicine, La Jolla, CA 92093-0723, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kisseleva
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, Moores Cancer Center, UCSD School of Medicine, La Jolla, CA 92093-0723, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Diaz-Meco
authors.affiliation: Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018167:Receptors, Calcitriol / Q000378:metabolism*; D047488:Retinoid X Receptors / Q000378:metabolism; D000071456:Sequestosome-1 Protein / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; C579457:VDR protein, human
keywords: fibrosis; hepatic stellate cells; hepatocellular carcinoma; inflammation; liver cancer; non-alcoholic steatohepatitis; nuclear receptors; p62; sequestosome-1; vitamin D receptor