CoChat
Sign Up
Cited by 1,110Liver Disease Diagnosis and TreatmentInflammasome and immune disordersLiver physiology and pathology

The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.

NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice

Open access
Mridha, Auvro R., Wree, Alexander, Robertson, Avril A.B., Yeh, Matthew M., Johnson, Casey D., Van Rooyen, Derrick M., Haczeyni, Fahrettin, Teoh, Narci C.-H., Savard, Christopher, Ioannou, George N., Masters, Seth L., Schroder, Kate, Cooper, Matthew A., Feldstein, Ariel E., Farrell, Geoffrey C.·2017·Journal of Hepatology
DOI 10.1016/j.jhep.2017.01.022PMC PMC6536116
Open this paper in CoChat — free account

Abstract

Background & aims NOD-like receptor protein 3 (NLRP3) inflammasome activation occurs in Non-alcoholic fatty liver disease (NAFLD). We used the first small molecule NLRP3 inhibitor, MCC950, to test whether inflammasome blockade alters inflammatory recruitment and liver fibrosis in two murine models of steatohepatitis.Methods We fed foz/foz and wild-type mice an atherogenic diet for 16weeks, gavaged MCC950 or vehicle until 24weeks, then determined NAFLD phenotype. In mice fed an methionine/choline deficient (MCD) diet, we gavaged MCC950 or vehicle for 6weeks and determined the effects on liver fibrosis.Results In vehicle-treated foz/foz mice, hepatic expression of NLRP3, pro-IL-1β, active caspase-1 and IL-1β increased at 24weeks, in association with cholesterol crystal formation and NASH pathology; plasma IL-1β, IL-6, MCP-1, ALT/AST all increased. MCC950 treatment normalized hepatic caspase 1 and IL-1β expression, plasma IL-1β, MCP-1 and IL-6, lowered ALT/AST, and reduced the severity of liver inflammation including designation as NASH pathology, and liver fibrosis. In vitro, cholesterol crystals activated Kupffer cells and macrophages to release IL-1β; MCC950 abolished this, and the associated neutrophil migration. MCD diet-fed mice developed fibrotic steatohepatitis; MCC950 suppressed the increase in hepatic caspase 1 and IL-1β, lowered numbers of macrophages and neutrophils in the liver, and improved liver fibrosis.Conclusion MCC950, an NLRP3 selective inhibitor, improved NAFLD pathology and fibrosis in obese diabetic mice. This is potentially attributable to the blockade of cholesterol crystal-mediated NLRP3 activation in myeloid cells. MCC950 reduced liver fibrosis in MCD-fed mice. Targeting NLRP3 is a logical direction in pharmacotherapy of NASH.Lay summary Fatty liver disease caused by being overweight with diabetes and a high risk of heart attack, termed non-alcoholic steatohepatitis (NASH), is the most common serious liver disease with no current treatment. There could be several causes of inflammation in NASH, but activation of a protein scaffold within cells termed the inflammasome (NLRP3) has been suggested to play a role. Here we show that cholesterol crystals could be one pathway to activate the inflammasome in NASH. We used a drug called MCC950, which has already been shown to block NLRP3 activation, in an attempt to reduce liver injury in NASH. This drug partly reversed liver inflammation, particularly in obese diabetic mice that most closely resembles the human context of NASH. In addition, such dampening of liver inflammation in NASH achieved with MCC950 partly reversed liver scarring, the process that links NASH to the development of cirrhosis.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.jhep.2017.01.022

Cites

49 of 49 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Show all 49 references

Cited by

Sorted by citations

Related

See all

Metadata

Authors
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., Masters, S. L., Schroder, K., Cooper, M. A., Feldstein, A. E., & Farrell, G. C.
Affiliations
  • Australian National University (AU)
  • University of California San Diego (US)
  • The University of Queensland (AU)
  • University of Washington (US)
  • Walter and Eliza Hall Institute of Medical Research (AU)
Corresponding author
Farrell, Geoffrey C.
ORCID
Venue
Journal of Hepatology
Publisher
Elsevier BV
Published
2017-05
Volume
66
Issue
5
Pages
1037-1046
ISSN
0168-8278 (ISSN-L)
DOI
10.1016/j.jhep.2017.01.022
PMC
PMC6536116
OpenAlex
W2585046292
Cited by
1,110
References
49
Citations by year
2026: 117 · 2025: 147 · 2024: 126 · 2023: 150 · 2022: 160 · 2021: 143 · 2020: 121 · 2019: 61 · 2018: 70 · 2017: 14
FWCI
57.20
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of Hepatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • ANU Open Research (Australian National University) (submittedVersion, cc-by-nc-nd)
  • RWTH Publications (RWTH Aachen) (submittedVersion)
Funders
  • National Institute on Alcohol Abuse and Alcoholism (U01AA022489, R21AA023574)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK113592)
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, MCC950, nonalcoholic steatohepatitis, liver fibrosis, liver inflammation, IL-1β, caspase-1, cholesterol crystals, Kupffer cells, macrophages, neutrophil migration, methionine-choline-deficient diet, atherogenic diet, myeloid cells
MeSH terms
NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Disease Models, Animal, Female, Furans, Hepatitis, Heterocyclic Compounds, 4 or More Rings, Indenes, Liver Cirrhosis, Experimental, Sulfonamides, Sulfones, NF-kappa B, Reactive Oxygen Species, Mice, Interleukin-1beta, Non-alcoholic Fatty Liver Disease

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review