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Non-alcoholic steatohepatitis pathogenesis: sublethal hepatocyte injury as a driver of liver inflammation
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A subset of patients with non-alcoholic fatty liver disease develop an inflammatory condition, termed non-alcoholic steatohepatitis (NASH). NASH is characterised by hepatocellular injury, innate immune cell-mediated inflammation and progressive liver fibrosis. The mechanisms whereby hepatic inflammation occurs in NASH remain incompletely understood, but appear to be linked to the proinflammatory microenvironment created by toxic lipid-induced hepatocyte injury, termed lipotoxicity. In this review, we discuss the signalling pathways induced by sublethal hepatocyte lipid overload that contribute to the pathogenesis of NASH. Furthermore, we will review the role of proinflammatory, proangiogenic and profibrotic hepatocyte-derived extracellular vesicles as disease biomarkers and pathogenic mediators during lipotoxicity. We also review the potential therapeutic strategies to block the feed-forward loop between sublethal hepatocyte injury and liver inflammation.
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“Caloric overload, steatosis, oxidative stress, ER stress and hepatocyte ‘lipoapotosis’ represent first steps in cell-cell communication, triggering the fibroinflammatory cycle.13,23”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [23]
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Metadata
- Authors
- Ibrahim, S. H., Hirsova, P., & Gores, G. J.
- Affiliations
- Mayo Clinic (US)
- Charles University (CZ)
- Corresponding author
- Gores, Gregory J
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2018-01-24
- Volume
- 67
- Issue
- 5
- Pages
- 963-972
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC5889737
- OpenAlex
- W2784619339
- Cited by
- 278
- References
- 89
- Citations by year
- 2026: 20 · 2025: 26 · 2024: 28 · 2023: 29 · 2022: 37 · 2021: 50 · 2020: 43 · 2019: 28 · 2018: 17
- FWCI
- 4.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Mayo Clinic
- Gilead Sciences
- MH CZ–DRO
- National Institute of Diabetes and Digestive and Kidney Diseases
- North American Society of Pediatric Gastroenterology Hepatology and Nutrition Young Investigator Award/Nestle Nutrition Award
- 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, lipotoxicity, lipid overload, liver inflammation, liver fibrosis, disease biomarkers, treatment options
- MeSH terms
- Animals, Hepatitis, Humans, Lipids, Liver, Signal Transduction, Hepatocytes, Non-alcoholic Fatty Liver Disease
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