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ASK1 inhibition reduces cell death and hepatic fibrosis in an Nlrp3 mutant liver injury model
Susanne Schuster-Gaul, … , Hal M. Hoffman, Ariel E. Feldstein
Susanne Schuster-Gaul, … , Hal M. Hoffman, Ariel E. Feldstein
Published January 30, 2020
Citation Information: JCI Insight. 2020;5(2):e123294. https://doi.org/10.1172/jci.insight.123294.
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Research Article Hepatology Therapeutics Article has an altmetric score of 3

ASK1 inhibition reduces cell death and hepatic fibrosis in an Nlrp3 mutant liver injury model

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Abstract

Hepatic inflammasome activation is considered a major contributor to liver fibrosis in NASH. Apoptosis signal–regulating kinase 1 (ASK1) is an apical mitogen-activated protein kinase that activates hepatic JNK and p38 to promote apoptosis, inflammation, and fibrosis. The aim of the current study was to investigate whether pharmacologic inhibition of ASK1 could attenuate hepatic fibrosis driven by inflammasome activation using gain-of-function NOD-like receptor protein 3 (Nlrp3) mutant mice. Tamoxifen-inducible Nlrp3 knock-in (Nlrp3A350V/+CreT-KI) mice and WT mice were administered either control chow diet or diet containing the selective ASK1 inhibitor GS-444217 for 6 weeks. Livers of Nlrp3-KI mice had increased inflammation, cell death, and fibrosis and increased phosphorylation of ASK1, p38, and c-Jun. GS-444217 reduced ASK1 pathway activation, liver cell death, and liver fibrosis. ASK1 inhibition resulted in a significant downregulation of genes involved in collagen production and extracellular matrix deposition, as well as in a reduced hepatic TNF-α expression. ASK1 inhibition also directly reduced LPS-induced gene expression of Collagen 1A1 (Col1a1) in hepatic stellate cells isolated from Nlrp3-KI mice. In conclusion, ASK1 inhibition reduced liver cell death and fibrosis downstream of inflammatory signaling induced by NLRP3. These data provide mechanistic insight into the antifibrotic mechanisms of ASK1 inhibition.

Authors

Susanne Schuster-Gaul, Lukas Jonathan Geisler, Matthew D. McGeough, Casey D. Johnson, Anna Zagorska, Li Li, Alexander Wree, Vivian Barry, Igor Mikaelian, Lily J. Jih, Bettina G. Papouchado, Grant Budas, Hal M. Hoffman, Ariel E. Feldstein

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Figure 5

Effects of ASK1 inhibition in isolated primary liver cells from Nlrp3-KI mice.

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Effects of ASK1 inhibition in isolated primary liver cells from Nlrp3-KI...
(A and B) Isolated primary Kupffer cells (A) and hepatic stellate cells (B) from Nlrp3-KI mice were treated with tamoxifen and LPS for 24 hours with our without preincubation of the ASK1 inhibitor GS-4997 (1 μM, 10 μM) and gene expression of Tnfa, Nlrp3, and Il1b in Kupffer cells and Col1a1 and Acta2 in hepatic stellate cells were analyzed. Data are expressed as the mean ± SEM of 3–4 individual mice and were normalized to WT. *P < 0.05 (1-way ANOVA with Bonferroni post hoc test).

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