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Interspecies NASH disease activity whole-genome profiling identifies a fibrogenic role of PPARα-regulated dermatopontin
Open accessAbstract
Nonalcoholic fatty liver disease prevalence is soaring with the obesity pandemic, but the pathogenic mechanisms leading to the progression toward active nonalcoholic steatohepatitis (NASH) and fibrosis, major causes of liver-related death, are poorly defined. To identify key components during the progression toward NASH and fibrosis, we investigated the liver transcriptome in a human cohort of NASH patients. The transition from histologically proven fatty liver to NASH and fibrosis was characterized by gene expression patterns that successively reflected altered functions in metabolism, inflammation, and epithelial-mesenchymal transition. A meta-analysis combining our and public human transcriptomic datasets with murine models of NASH and fibrosis defined a molecular signature characterizing NASH and fibrosis and evidencing abnormal inflammation and extracellular matrix (ECM) homeostasis. Dermatopontin expression was found increased in fibrosis, and reversal of fibrosis after gastric bypass correlated with decreased dermatopontin expression. Functional studies in mice identified an active role for dermatopontin in collagen deposition and fibrosis. PPARα activation lowered dermatopontin expression through a transrepressive mechanism affecting the Klf6/TGFβ1 pathway. Liver fibrotic histological damages are thus characterized by the deregulated expression of a restricted set of inflammation- and ECM-related genes. Among them, dermatopontin may be a valuable target to reverse the hepatic fibrotic process.
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“Through the use of bulk RNA-seq, liver gene signatures were derived from whole liver, isolated hepatocytes, isolated non-parenchymal cells, or plasma that correlated with various disease features and, in some cases, predicted the transition from MASLD to MASH (44, 116-122).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [122]
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Rom, O., Liu, Y., Liu, Z., Zhao, Y., Wu, J., Ghrayeb, A., Villacorta, L., Fan, Y., Chang, L., Wang, L., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aaz2841 · Cited by 301
The Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity
Van Herck, M. A., Weyler, J., Kwanten, W. J., Dirinck, E. L., De Winter, B. Y., Francque, S. M., & Vonghia, L. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00082 · Cited by 238
Self-citation
Metadata
- Authors
- Lefebvre, P., Lalloyer, F., Baugé, E., Pawlak, M., Gheeraert, C., Dehondt, H., Vanhoutte, J., Woitrain, E., Hennuyer, N., Mazuy, C., Bobowski-Gérard, M., Zummo, F. P., Derudas, B., Driessen, A., Hubens, G., Vonghia, L., Kwanten, W. J., Michielsen, P., Vanwolleghem, T., Eeckhoute, J., Verrijken, A., Van Gaal, L., Francque, S., & Staels, B.
- Affiliations
- University Lille, Inserm, CHU-Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.
- Inserm (FR)
- Department of Pathology,
- Department of Abdominal Surgery,
- Antwerp University Hospital (BE)
- University of Antwerp (BE)
- Department of Endocrinology, Diabetology and Metabolism, University Hospital Antwerp, Edegem, Belgium.
- Corresponding author
- Francque, Sven
- Staels, Bart
- ORCID
- Venue
- JCI Insight
- Published
- 2017-07-06
- Volume
- 2
- Issue
- 13
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC5499370
- OpenAlex
- W2731411640
- Cited by
- 117
- References
- 83
- Citations by year
- 2026: 5 · 2025: 9 · 2024: 17 · 2023: 15 · 2022: 19 · 2021: 18 · 2020: 14 · 2019: 8 · 2018: 11 · 2017: 1
- FWCI
- 7.28
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- JCI Insight (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Commission (305707)
- Agence Nationale de la Recherche (ANR-10-LABX-0046, ANR-10, ANR-10-LBEX-46)
- Institut National de la Santé et de la Recherche Médicale
- Fundacja na rzecz Nauki Polskiej
- Fondation pour la Recherche Médicale (Equipe labellisée, DEQ20150331724, DEQ20150331724)
- Fondation de France
- Narodowym Centrum Nauki
- Institute of Molecular and Cell Biology
- 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, dermatopontin, PPARα, extracellular matrix homeostasis, liver inflammation, epithelial-mesenchymal transition, gastric bypass, collagen deposition, liver transcriptome, fibrosis reversal
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