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ER Stress Cooperates with Hypernutrition to Trigger TNF-Dependent Spontaneous HCC Development
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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.
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“Several transgenic animals have been developed to study MASH pathogenesis, including those that overexpress urokinase-type plasminogen activator (MUP-uPA) (221) or sterol regulatory element-binding protein 1 (SREBP1) (222, 223).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [221]
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Metadata
- Authors
- Nakagawa, H., Umemura, A., Taniguchi, K., Font-Burgada, J., Dhar, D., Ogata, H., Zhong, Z., Valasek, M. A., Seki, E., Hidalgo, J., Koike, K., Kaufman, R. J., & Karin, M.
- Affiliations
- University of California San Diego (US)
- Kyushu University (JP)
- Universitat Autònoma de Barcelona (ES)
- The University of Tokyo (JP)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Karin, Michael
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2014-09
- Volume
- 26
- Issue
- 3
- Pages
- 331-343
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC4165611
- OpenAlex
- W2085390667
- Cited by
- 525
- References
- 38
- Citations by year
- 2026: 22 · 2025: 38 · 2024: 43 · 2023: 58 · 2022: 57 · 2021: 57 · 2020: 56 · 2019: 40 · 2018: 42 · 2017: 34 · 2016: 39 · 2015: 28 · 2014: 11
- FWCI
- 18.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Japan Society for the Promotion of Science (24390183)
- National Heart, Lung, and Blood Institute (R01HL052173, HL052173-16)
- National Cancer Institute (R01CA118165, CA155120-02, R01CA155120, P30CA023100, CA118165-06)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK088227, DK042394-18, DK088227-06)
- National Institute of Environmental Health Sciences (P42ES010337)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Keywords
- endoplasmic reticulum stress, overnutrition, hepatocellular carcinoma, nonalcoholic steatohepatitis, TNF-α, plasminogen activator, high-fat diet, insulin resistance, hepatic steatosis, inflammatory macrophages, lipogenesis
- MeSH terms
- Endoplasmic Reticulum Chaperone BiP, Animals, Cells, Cultured, Fatty Liver, Heat-Shock Proteins, Carcinoma, Hepatocellular, Liver Neoplasms, Experimental, Male, Mice, Transgenic, Tumor Necrosis Factor-alpha, Urokinase-Type Plasminogen Activator, Signal Transduction, Overnutrition, Tumor Burden, Receptors, Tumor Necrosis Factor, Type I, Lipogenesis, Mice, Diet, High-Fat, Endoplasmic Reticulum Stress
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