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

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

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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Crossref · 10.1194/jlr.r066357

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  • In both NAFLD and cholestasis, failed or inadequate metabolic adaptation to substrate overload results in sublethal cell stress or cell death with release of mediators and extracellular vesicles driving inflammation and fibrosis.

    “In both scenarios failed or inadequate metabolic adaptation to substrate overload results in sublethal cell stress or even cell death with release of mediators and extracellular vesicles driving inflammation and fibrosis15–17”

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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
Venue
Journal of Lipid Research
Publisher
Elsevier BV
Published
2016-10
Volume
57
Issue
10
Pages
1758-1770
ISSN
0022-2275 (ISSN-L)
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
Open access
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 › Epidemiology › 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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