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NLRP3 inflammasome activation is required for fibrosis development in NAFLD
Open accessAbstract
NLR inflammasomes, caspase 1 activation platforms critical for processing key pro-inflammatory cytokines, have been implicated in the development of nonalcoholic fatty liver disease (NAFLD). As the direct role of the NLRP3 inflammasome remains unclear, we tested effects of persistent NLRP3 activation as a contributor to NAFLD development and, in particular, as a modulator of progression from benign hepatic steatosis to steatohepatitis during diet-induced NAFLD. Gain of function tamoxifen-inducible Nlrp3 knock-in mice allowing for in vivo temporal control of NLRP3 activation and loss of function Nlrp3 knockout mice were placed on short-term choline-deficient amino acid-defined (CDAA) diet, to induce isolated hepatic steatosis or long-term CDAA exposure, to induce severe steatohepatitis and fibrosis, respectively. Expression of NLRP3 associated proteins was assessed in liver biopsies of a well-characterized group of patients with the full spectrum of NAFLD. Nlrp3(-/-) mice were protected from long-term feeding CDAA-induced hepatomegaly, liver injury, and infiltration of activated macrophages. More importantly, Nlrp3(-/-) mice showed marked protection from CDAA-induced liver fibrosis. After 4 weeks on CDAA diet, wild-type (WT) animals showed isolated hepatic steatosis while Nlrp3 knock-in mice showed severe liver inflammation, with increased infiltration of activated macrophages and early signs of liver fibrosis. In the liver samples of patients with NAFLD, inflammasome components were significantly increased in those patients with nonalcoholic steatohepatitis (NASH) when compared to those with non-NASH NAFLD with mRNA levels of pro-IL1 beta correlated to levels of COL1A1. Our study uncovers a crucial role for the NLRP3 inflammasome in the development of NAFLD. These findings may lead to novel therapeutic strategies aimed at halting the progression of hepatic steatosis to the more severe forms of this disease. Key message: Mice with NLRP3 inflammasome loss of function are protected from diet-induced steatohepatitis. NLRP3 inflammasome gain of function leads to early and severe onset of diet-induced steatohepatitis in mice. Patients with severe NAFLD exhibit increased levels of NLRP3 inflammasome components and levels of pro-IL1β mRNA correlate with the expression of COL1A1.
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“Sen cells showed altered lipid-transport and lipoprotein-remodelling traits (Fig. 3a), consistent with the ability of oxidative stress to generate lipotoxicity that triggers inflammation and fibrosis30.”
From Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration (2023) · cites this paper as [30]
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“Either in patients with NASH or animal models, the expression of inflammasome components was increased, indicating the potential role in the pathogenesis of liver injury [226,227,288,289,290,291].”
From Gut-pancreas-liver Axis as a target for treatment of NAFLD/NASH (2020) · cites this paper as [289]
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Citations
Cites
Design and validation of a histological scoring system for nonalcoholic fatty liver disease†
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Self-citationThe NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance
Vandanmagsar, B., Youm, Y.-H., Ravussin, A., Galgani, J. E., Stadler, K., Mynatt, R. L., Ravussin, E., Stephens, J. M., & Dixit, V. D. (2011) · Nature Medicine · doi:10.1038/nm.2279 · Cited by 2,655
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Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity
Henao-Mejia, J., Elinav, E., Jin, C., Hao, L., Mehal, W. Z., Strowig, T., Thaiss, C. A., Kau, A. L., Eisenbarth, S. C., Jurczak, M. J., et al. (2012) · Nature · doi:10.1038/nature10809 · Cited by 2,435
Self-citationFatty acid–induced NLRP3-ASC inflammasome activation interferes with insulin signaling
Wen, H., Gris, D., Lei, Y., Jha, S., Zhang, L., Huang, M. T.-H., Brickey, W. J., & Ting, J. P.-Y. (2011) · Nature Immunology · doi:10.1038/ni.2022 · Cited by 1,698
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The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)
Buzzetti, E., Pinzani, M., & Tsochatzis, E. A. (2016) · Metabolism · doi:10.1016/j.metabol.2015.12.012 · Cited by 3,119
Targeting the NLRP3 inflammasome in inflammatory diseases
Mangan, M. S. J., Olhava, E. J., Roush, W. R., Seidel, H. M., Glick, G. D., & Latz, E. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.97 · Cited by 1,885
Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives
Roehlen, N., Crouchet, E., & Baumert, T. F. (2020) · Cells · doi:10.3390/cells9040875 · Cited by 1,237
Dietary lipids, gut microbiota and lipid metabolism
Schoeler, M., & Caesar, R. (2019) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-019-09512-0 · Cited by 1,163
NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice
Mridha, A. R., Wree, A., Robertson, A. A. B., Yeh, M. M., Johnson, C. D., Van Rooyen, D. M., Haczeyni, F., Teoh, N. C.-H., Savard, C., Ioannou, G. N., et al. (2017) · Journal of Hepatology · doi:10.1016/j.jhep.2017.01.022 · Cited by 1,110
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Metadata
- Authors
- Wree, A., McGeough, M. D., Peña, C. A., Schlattjan, M., Li, H., Inzaugarat, M. E., Messer, K., Canbay, A., Hoffman, H. M., & Feldstein, A. E.
- Affiliations
- University of California San Diego (US)
- Essen University Hospital (DE)
- Corresponding author
- Feldstein, Ariel E.
- ORCID
- Venue
- Journal of Molecular Medicine
- Published
- 2014-05-28
- Volume
- 92
- Issue
- 10
- Pages
- 1069-1082
- ISSN
- 0946-2716 (ISSN-L)
- 1432-1440
- PMC
- PMC4349416
- OpenAlex
- W1977508200
- Cited by
- 486
- References
- 43
- Citations by year
- 2026: 18 · 2025: 31 · 2024: 31 · 2023: 64 · 2022: 66 · 2021: 63 · 2020: 69 · 2019: 27 · 2018: 37 · 2017: 33 · 2016: 27 · 2015: 17 · 2014: 3
- FWCI
- 20.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Americanae (AECID Library) (submittedVersion, cc-by-nc-sa)
- eScholarship (California Digital Library) (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (U01AA022489)
- National Cancer Institute (P30CA023100)
- National Institute of Allergy and Infectious Diseases (AI52430, R01AI052430)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK082451, R01DK076852, DK082451, DK-076852)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- NLRP3 inflammasome, non-alcoholic fatty liver disease, liver fibrosis, steatohepatitis, hepatic steatosis, NLRP3 knockout mice, pro-IL-1β, COL1A1, macrophage infiltration, liver inflammation, caspase-1
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Collagen Type I, alpha 1 Chain, Animals, Carrier Proteins, Female, Fibrosis, Humans, Liver, Male, Mice, Transgenic, RNA, Messenger, Collagen Type I, Inflammasomes, Non-alcoholic Fatty Liver Disease
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