Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis
Open accessAbstract
Nonalcoholic steatohepatitis (NASH) is emerging as a leading cause of chronic liver disease. However, therapeutic options are limited by incomplete understanding of the mechanisms of NASH fibrosis, which is mediated by activation of hepatic stellate cells (HSCs). In humans, human genetic studies have shown that hypomorphic variations in MERTK, encoding the macrophage c-mer tyrosine kinase (MerTK) receptor, provide protection against liver fibrosis, but the mechanisms remain unknown. We now show that holo- or myeloid-specific Mertk targeting in NASH mice decreases liver fibrosis, congruent with the human genetic data. Furthermore, ADAM metallopeptidase domain 17 (ADAM17)-mediated MerTK cleavage in liver macrophages decreases during steatosis to NASH transition, and mice with a cleavage-resistant MerTK mutant have increased NASH fibrosis. Macrophage MerTK promotes an ERK-TGFβ1 pathway that activates HSCs and induces liver fibrosis. These data provide insights into the role of liver macrophages in NASH fibrosis and provide a plausible mechanism underlying MERTK as a genetic risk factor for NASH fibrosis.
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Deleting macrophage MerTK does not impair liver macrophage efferocytosis in FPC or HF-CDAA MASH models.
“The finding with Mertk is consistent with our previous demonstration that liver macrophage efferocytosis in mice fed the MASH-inducing fructose-palmitate-cholesterol (FPC) diet for 16 weeks was not impaired by deletion of macrophage MerTK (33), and we now show similar results using the HD-CDAA MASH model (fig. S1C).”
From Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction–associated steatohepatitis (2025) · cites this paper as [33]
ADAM17 cleaves MerTK to control macrophage inflammatory responses in steatotic livers, but this compensation fails in NASH possibly due to reduced availability of HSC-supplied vitamin A necessary to stimulate ADAM17.
“ADAM17 cleaves MerTK to control macrophage inflammatory responses in steatotic livers, but this compensation fails in NASH – possibly due to reduced availability of HSC-supplied vitamin A (which is depleted when HSCs activate) that is necessary to stimulate ADAM17 (100).”
From Hepatic Stellate Cell-Immune Interactions in NASH (2022) · cites this paper as [100]
Other macrophage-secreted cytokines that may promote HSC activation include PDGF, TNFα, and IL-1β.
“Other macrophage-secreted cytokines that may promote HSC activation include PDGF, tumor necrosis factor alpha (TNFα), and interleukin 1 beta ( IL-1β) (65-69).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [69]
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References 100 · Cited by 266
- Authors
- Cai, B., Dongiovanni, P., Corey, K. E., Wang, X., Shmarakov, I. O., Zheng, Z., Kasikara, C., Davra, V., Meroni, M., Chung, R. T., Rothlin, C. V., Schwabe, R. F., Blaner, W. S., Birge, R. B., Valenti, L., & Tabas, I.
- Affiliations
- Columbia University Irving Medical Center (US)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Harvard University (US)
- Rutgers, The State University of New Jersey (US)
- Yale University (US)
- University of Milan (IT)
- Corresponding author
- Cai, Bishuang
- Tabas, Ira
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2020-02
- Volume
- 31
- Issue
- 2
- Pages
- 406-421.e7
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC7004886
- OpenAlex
- W2995961563
- Cited by
- 266
- References
- 100
- Citations by year
- 2026: 39 · 2025: 47 · 2024: 40 · 2023: 36 · 2022: 43 · 2021: 36 · 2020: 24 · 2019: 1
- FWCI
- 19.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Funders
- American Heart Association
- American Society of Hematology (19CDA34660043)
- American Liver Foundation
- National Heart, Lung, and Blood Institute (AI136715, DK078772, DK108370, T32HL007343)
- National Institute of Diabetes and Digestive and Kidney Diseases (5P30DK063608, RU-301)
- National Institutes of Health (1K99DK115778)
- Howard Hughes Medical Institute
- European Commission
- Associazione Italiana per la Ricerca sul Cancro (16888)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
- 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, MERTK, hepatic stellate cells, hepatic macrophages, ADAM17, receptor cleavage, steatosis, genetic risk factors
- MeSH terms
- ADAM17 Protein, c-Mer Tyrosine Kinase, Animals, Cell Line, Chronic Disease, Humans, Liver, Liver Cirrhosis, Macrophages, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, Rats, Non-alcoholic Fatty Liver Disease
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