title: ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development.
abstract: Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of viral hepatitis, insulin resistance, hepatosteatosis, and nonalcoholic steatohepatitis (NASH), disorders that increase risk of hepatocellular carcinoma (HCC). To determine whether and how ER stress contributes to obesity-driven hepatic tumorigenesis we fed wild-type (WT) and MUP-uPA mice, in which hepatocyte ER stress is induced by plasminogen activator expression, with high-fat diet. Although both strains were equally insulin resistant, the MUP-uPA mice exhibited more liver damage, more immune infiltration, and increased lipogenesis and, as a result, displayed classical NASH signs and developed typical steatohepatitic HCC. Both NASH and HCC development were dependent on TNF produced by inflammatory macrophages that accumulate in the MUP-uPA liver in response to hepatocyte ER stress.
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Hayato
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Umemura
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Font-Burgada
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA.
authors.forename: Debanjan
authors.initials: D
authors.lastname: Dhar
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Hisanobu
authors.initials: H
authors.lastname: Ogata
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Zhong
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Valasek
authors.affiliation: Department of Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA.
authors.forename: Ekihiro
authors.initials: E
authors.lastname: Seki
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences, Universitat Autonoma de Barcelona, Bellaterra, 08193 Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Hidalgo
authors.affiliation: Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Koike
authors.affiliation: Program in Degenerative Diseases, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Pathology, School of Medicine, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA. Electronic address: karinoffice@ucsd.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D050155:Lipogenesis; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D044343:Overnutrition / Q000150:complications*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D014568:Urokinase-Type Plasminogen Activator