Cited by 679Liver Disease Diagnosis and TreatmentLiver physiology and pathologyLiver Diseases and Immunity

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Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis

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Schwabe, Robert F., Tabas, Ira, Pajvani, Utpal B.·2020·Gastroenterology

DOI 10.1053/j.gastro.2019.11.311PMC PMC7682538

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Abstract

Nonalcoholic fatty liver disease is the most prevalent liver disease worldwide, affecting 20%-25% of the adult population. In 25% of patients, nonalcoholic fatty liver disease progresses to nonalcoholic steatohepatitis (NASH), which increases the risk for the development of cirrhosis, liver failure, and hepatocellular carcinoma. In patients with NASH, liver fibrosis is the main determinant of mortality. Here, we review how interactions between different liver cells culminate in fibrosis development in NASH, focusing on triggers and consequences of hepatocyte-macrophage-hepatic stellate cell (HSC) crosstalk. We discuss pathways through which stressed and dead hepatocytes instigate the profibrogenic crosstalk with HSC and macrophages, including the reactivation of developmental pathways such as TAZ, Notch, and hedgehog; how clearance of dead cells in NASH via efferocytosis may affect inflammation and fibrogenesis; and insights into HSC and macrophage heterogeneity revealed by single-cell RNA sequencing. Finally, we summarize options to therapeutically interrupt this profibrogenic hepatocyte-macrophage-HSC network in NASH.

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Authors: Schwabe, R. F., Tabas, I., & Pajvani, U. B.
Affiliations: Columbia University Irving Medical Center (US)
Columbia University (US)
Corresponding author: Schwabe, Robert F.
ORCID: Schwabe, Robert F.
Tabas, Ira
Pajvani, Utpal B.
Venue: Gastroenterology
Publisher: Elsevier BV
Published: 2020-05
Volume: 158
Issue: 7
Pages: 1913-1928
ISSN: 0016-5085 (ISSN-L)
DOI: 10.1053/j.gastro.2019.11.311
PMC: PMC7682538
OpenAlex: W3005214954
Cited by: 671
References: 169
Citations by year: 2026: 82 · 2025: 121 · 2024: 138 · 2023: 131 · 2022: 117 · 2021: 53 · 2020: 27
FWCI: 12.15
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: Gastroenterology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health
Topics: Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Keywords: nonalcoholic steatohepatitis, liver fibrosis, hepatic stellate cells, macrophages, hepatocyte death, efferocytosis, TAZ, Notch signaling, Hedgehog signaling, single-cell RNA sequencing, antifibrotic therapy, non-alcoholic fatty liver disease
MeSH terms: Animals, Cell Communication, Extracellular Matrix, Humans, Liver, Liver Cirrhosis, Macrophages, Signal Transduction, Cell Death, Hepatocytes, Hepatic Stellate Cells, Non-alcoholic Fatty Liver Disease

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Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis

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