Cited by 270Liver Disease Diagnosis and TreatmentLiver physiology and pathologyDrug-Induced Hepatotoxicity and Protection

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Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis

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Hirsova, Petra, Ibrabim, Samar H., Gores, Gregory J., Malhi, Harmeet·2016·Journal of Lipid Research

DOI 10.1194/jlr.r066357PMC PMC5036373

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Abstract

The accumulation of lipids is a histologic and biochemical hallmark of obesity-associated nonalcoholic fatty liver disease (NAFLD). A subset of NALFD patients develops progressive liver disease, termed nonalcoholic steatohepatitis, which is characterized by hepatocellular apoptosis and innate immune system-mediated inflammation. These responses are orchestrated by signaling pathways that can be activated by lipids, directly or indirectly. In this review, we discuss palmitate- and lysophosphatidylcholine (LPC)-induced upregulation of p53-upregulated modulator of apoptosis and cell-surface expression of the death receptor TNF-related apoptosis-inducing ligand receptor 2. Next, we review the activation of stress-induced kinases, mixed lineage kinase 3, and c-Jun N-terminal kinase, and the activation of endoplasmic reticulum stress response and its downstream proapoptotic effector, CAAT/enhancer binding homologous protein, by palmitate and LPC. Moreover, the activation of these stress signaling pathways is linked to the release of proinflammatory, proangiogenic, and profibrotic extracellular vesicles by stressed hepatocytes. This review discusses the signaling pathways induced by lethal and sublethal lipid overload that contribute to the pathogenesis of NAFLD.

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Ibrahim, 2016, Mixed lineage kinase 3 mediates release of C-X-C motif ligand 10-bearing chemotactic extracellular vesicles from lipotoxic hepatocytes, Hepatology., 63:, 731, 10.1002/hep.28252 · DOI · Paper page

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Authors: Hirsova, P., Ibrabim, S. H., Gores, G. J., & Malhi, H.
Affiliations: Mayo Clinic (US)
Corresponding author: Gores, Gregory J.
Malhi, Harmeet
ORCID: Hirsova, Petra
Gores, Gregory J.
Malhi, Harmeet
Venue: Journal of Lipid Research
Publisher: Elsevier BV
Published: 2016-10
Volume: 57
Issue: 10
Pages: 1758-1770
ISSN: 0022-2275 (ISSN-L)
DOI: 10.1194/jlr.r066357
PMC: PMC5036373
OpenAlex: W2321179708
Cited by: 270
References: 141
Citations by year: 2026: 17 · 2025: 27 · 2024: 22 · 2023: 28 · 2022: 35 · 2021: 36 · 2020: 35 · 2019: 23 · 2018: 28 · 2017: 16 · 2016: 3
FWCI: 3.14
Type: journal article
Language: en
Update notices: correction (2017-01-01)
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 1448 d)
Locations: Journal of Lipid Research (publishedVersion, cc-by)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Office of Extramural Research, National Institutes of Health (DK97178, DK41876, KL2TR000136-09)
American Liver Foundation
Topics: Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords: nonalcoholic steatohepatitis, non-alcoholic fatty liver disease, hepatocyte apoptosis, lipid overload, palmitate, lysophosphatidylcholine, TRAIL receptor 2, MLK3, c-Jun N-terminal kinase, endoplasmic reticulum stress, CHOP, extracellular vesicles, liver inflammation, liver fibrosis, obesity
MeSH terms: Mitogen-Activated Protein Kinase Kinase Kinase 11, Animals, Humans, Lysophosphatidylcholines, Palmitates, Stress, Physiological, Up-Regulation, Tumor Suppressor Protein p53, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, CCAAT-Enhancer-Binding Proteins, Hepatocytes, TNF Receptor-Associated Factor 2, JNK Mitogen-Activated Protein Kinases, Non-alcoholic Fatty Liver Disease

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Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis

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