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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is a multifactorial disease, characterized by a broad spectrum of symptoms ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with fibrosis, liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC) [1]
IHC analysis showed a significant upregulation of nuclear phosphorylated c-Jun (P–c-Jun) in NOD-like receptor protein 3 (Nlrp3)-KI liver, which was localized to focal areas of hepatocyte injury and cell death (Figure 1F)
We investigated whether pharmacological inhibition of Apoptosis signal–regulating kinase 1 (ASK1) could reduce the progression of hepatic fibrosis in Nlrp3 mutant mice
Summary
Nonalcoholic fatty liver disease (NAFLD) is a multifactorial disease, characterized by a broad spectrum of symptoms ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) with fibrosis, liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC) [1]. Because liver fibrosis is considered a strong predictor of mortality and morbidity in patients with NASH [6,7,8], there is an urgent medical need to identify novel therapies, which can reduce the progression of hepatic fibrosis in this growing population of patients. Apoptosis signal–regulating kinase 1 (ASK1) is a ubiquitously expressed apical mitogen-activated kinase kinase kinase (MAP3K) that is activated by pathological stimuli that exist in human NASH liver, including oxidative and ER stress, and proinflammatory stimuli such as TNF-α and LPS [9,10,11,12]. ASK1 phosphorylates MAP2K-3, -4, -6, and -7, which in turn phosphorylate and activate effector MAPKs p38 and c-Jun N-terminal kinase (JNK) to promote apoptosis, inflammatory cytokine expression, and induction of fibrogenic genes in the liver [13, 14]. Emerging data have revealed that the ASK1-p38/ JNK pathway is increased in livers of patients with NASH and that ASK1 plays a causal role in NASH pathogenesis in murine models [15, 16]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
