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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Bulk RNA-seq liver gene signatures from whole liver, isolated hepatocytes, non-parenchymal cells, or plasma correlate with disease features and sometimes predict transition from MASLD to MASH.
“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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Nonalcoholic steatohepatitis: the role of peroxisome proliferator-activated receptors
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The Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity
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Self-citationFound in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH)
Wang, S., & Friedman, S. L. (2023) · Science Translational Medicine · doi:10.1126/scitranslmed.adi0759 · Cited by 158 · see citing works
A human multi-lineage hepatic organoid model for liver fibrosis
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QRICH1 dictates the outcome of ER stress through transcriptional control of proteostasis
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Hepatocyte TLR4 triggers inter-hepatocyte Jagged1/Notch signaling to determine NASH-induced fibrosis
Yu, J., Zhu, C., Wang, X., Kim, K., Bartolome, A., Dongiovanni, P., Yates, K. P., Valenti, L., Carrer, M., Sadowski, T., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abe1692 · Cited by 132 · see citing works
Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease
Fujiwara, N., Kubota, N., Crouchet, É., Koneru, B., Marquez, C. A., Jajoriya, A. K., Panda, G., Qian, T., Zhu, S., Goossens, N., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abo4474 · Cited by 124 · see citing works
Hepatic sexual dimorphism — implications for non-alcoholic fatty liver disease
Lefèbvre, P., & Staels, B. (2021) · Nature Reviews Endocrinology · doi:10.1038/s41574-021-00538-6 · Cited by 114 · see citing works
Self-citationCD4+ T cell activation and inflammation in NASH-related fibrosis
Zhou, Y., Zhang, H., Yao, Y., Zhang, X., Guan, Y., & Zheng, F. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.967410 · Cited by 110 · see citing works
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Transcriptional Dynamics of Hepatic Sinusoid‐Associated Cells After Liver Injury
Terkelsen, M. K., Bendixen, S. M., Hansen, D., Scott, E. A. H., Moeller, A. F., Nielsen, R., Mandrup, S., Schlosser, A. G., Andersen, T. L., Sørensen, G. L., et al. (2020) · Hepatology · doi:10.1002/hep.31215 · Cited by 104 · see citing works
Mapping the molecular signatures of diet-induced NASH and its regulation by the hepatokine Tsukushi
Xiong, X., Wang, Q., Wang, S., Zhang, J., Liu, T., Guo, L., Yu, Y., & Lin, J. D. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2018.12.004 · Cited by 100 · see citing works
Transcriptional regulation of Hepatic Stellate Cell activation in NASH
Marcher, A.-B., Bendixen, S. M., Terkelsen, M. K., Hohmann, S. S., Hansen, M. H., Larsen, B. D., Mandrup, S., Dimke, H., Detlefsen, S., & Ravnskjaer, K. (2019) · Scientific Reports · doi:10.1038/s41598-019-39112-6 · Cited by 95 · see citing works
Molecular characterization and cell type composition deconvolution of fibrosis in NAFLD
Pantano, L., Agyapong, G., Shen, Y., Zhuo, Z., Fernández-Albert, F., Rust, W., Knebel, D., Hill, J., Boustany, C., Doerner, J. F., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-96966-5 · Cited by 94 · see citing works
Serum amyloid A1 exacerbates hepatic steatosis via TLR4-mediated NF-κB signaling pathway
Jiang, B., Wang, D., Hu, Y., Li, W., Liu, F., Zhu, X., Li, X., Zhang, H., Bai, H., Yang, Q., et al. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101462 · Cited by 90 · see citing works
Krüppel-Like Factors in Metabolic Homeostasis and Cardiometabolic Disease
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Hepatic Molecular Signatures Highlight the Sexual Dimorphism of Nonalcoholic Steatohepatitis (NASH)
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Self-citationReprogramming of Hepatic Metabolism and Microenvironment in Nonalcoholic Steatohepatitis
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MASLD/MASH and type 2 diabetes: Two sides of the same coin? From single PPAR to pan-PPAR agonists
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Self-citationMulti-Omics Insights into Functional Alterations of the Liver in Insulin-Deficient Diabetes Mellitus
Backman, M., Flenkenthaler, F., Blutke, A., Dahlhoff, M., Ländström, E., Renner, S., Philippou‐Massier, J., Krebs, S., Rathkolb, B., Prehn, C. P., et al. (2018) · Molecular Metabolism · doi:10.1016/j.molmet.2019.05.011 · Cited by 40 · see citing works
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GARP on hepatic stellate cells is essential for the development of liver fibrosis
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Incretin combination therapy for the treatment of non-alcoholic steatohepatitis
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Self-citationPPARα and NCOR/SMRT corepressor network in liver metabolic regulation
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Selenotranscriptome Network in Non-alcoholic Fatty Liver Disease
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Tumor-associated neutrophils attenuate the immunosensitivity of hepatocellular carcinoma
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Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis
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DNMT3a-dermatopontin axis suppresses breast cancer malignancy via inactivating YAP
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Reciprocal Regulation of Hepatic TGF-β1 and Foxo1 Controls Gluconeogenesis and Energy Expenditure
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Hepatic adaptation to chronic metabolic stress primes tumorigenesis
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Emerging Insights into the Role of BDNF on Health and Disease in Periphery
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Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome
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Systematic Analysis of Long Non-Coding RNA Genes in Nonalcoholic Fatty Liver Disease
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Nuclear receptors: pathophysiological mechanisms and drug targets in liver disease
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Hepatic‐specific Pgc‐1α ablation drives fibrosis in a MASH model
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Translational Aspects of Diet and Non-Alcoholic Fatty Liver Disease
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SARS-CoV-2 receptor ACE2 is upregulated by fatty acids in human MASH
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A Positive Loop Formed by SOX11 and Periostin Upregulates TGF-β Signals Leading to Skin Fibrosis
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Comprehensive meta-analysis reveals distinct gene expression signatures of MASLD progression
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EMP1 as a Potential Biomarker in Liver Fibrosis: A Bioinformatics Analysis
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- 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 › Epidemiology › 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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