ArticleJournal of cellular biochemistry2017
Mixed Lineage Kinase 3 Mediates the Induction of CXCL10 by a STAT1-Dependent Mechanism During Hepatocyte Lipotoxicity.
Article in Journal of cellular biochemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 51 citations in OpenAlex.
- A Modular Liver-Microbial Microfluidic Platform to Evaluate Therapeutic and Adverse Effects of Microbial Metabolites.Advanced healthcare materials · 2026Article
- The Pathophysiological Interrelationship Between Metabolic Dysfunction-Associated Steatotic Liver Disease and Cardiovascular Disease.Antioxidants (Basel, Switzerland) · 2026Review
- Chemokines and chemokine receptors in metabolic dysfunction-associated steatohepatitis: pathogenic mechanisms and clinical implications.Cellular & molecular biology letters · 2026Review
- A Novel Role of the LINC01270/miR-326/LDOC1 Axis in Proinflammatory Response Regulation via STAT1 Modulation in THP-1 Cells.International journal of molecular sciences · 2026Article
- Identification of the E3 ligase TRIM21 as a crucial regulator of STAT1 in metabolic dysfunction-associated steatohepatitis.Cell communication and signaling : CCS · 2026Article
- Zebrafish model of palmitic acid induced MAFLD recapitulates pathways conserved in mice and humans.Scientific reports · 2025Article
- Extracellular vesicles in metabolic dysfunction-associated steatotic liver disease: From intercellular signaling to clinical translation.World journal of hepatology · 2025Review
- The role of extracellular vesicles in non-alcoholic steatohepatitis: Emerging mechanisms, potential therapeutics and biomarkers.Journal of advanced research · 2025Review
- Article
- Toxoplasma gondii IST suppresses inflammatory and apoptotic responses by inhibiting STAT1-mediated signaling in IFN-γ/TNF-α-stimulated hepatocytes.Parasites, hosts and diseases · 2024Article
- Energetic Stress-Induced Metabolic Regulation by Extracellular Vesicles.Comprehensive Physiology · 2023Article
- Article
- Non-Parenchymal Cells and the Extracellular Matrix in Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease.Cancers · 2023Review
- Mechanism and Therapeutic Targets of c-Jun-N-Terminal Kinases Activation in Nonalcoholic Fatty Liver Disease.Biomedicines · 2022Review
- Chronic Inflammation-A Link between Nonalcoholic Fatty Liver Disease (NAFLD) and Dysfunctional Adipose Tissue.Medicina (Kaunas, Lithuania) · 2022Review
- Article
- Macrophagic Extracellular Vesicle CXCL2 Recruits and Activates the Neutrophil CXCR2/PKC/NOX4 Axis in Sepsis.Journal of immunology (Baltimore, Md. : 1950) · 2021Article
- Role of extracellular vesicles in liver diseases and their therapeutic potential.Advanced drug delivery reviews · 2021Review
- Sinusoidal endotheliopathy in nonalcoholic steatohepatitis: therapeutic implications.American journal of physiology. Gastrointestinal and liver physiology · 2021Review
- Lipid-induced endothelial vascular cell adhesion molecule 1 promotes nonalcoholic steatohepatitis pathogenesis.The Journal of clinical investigation · 2021Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Saturated fatty acids (SFA) and their toxic metabolites contribute to hepatocyte lipotoxicity in nonalcoholic steatohepatitis (NASH). We previously reported that hepatocytes, under lipotoxic stress, express the potent macrophage chemotactic ligand C-X-C motif chemokine 10 (CXCL10), and release CXCL10-enriched extracellular vesicles (EV) by a mixed lineage kinase (MLK) 3-dependent mechanism. In the current study, we sought to examine the signaling pathway responsible for CXCL10 induction during hepatocyte lipotoxicity. Here, we demonstrate a role for signal transducer and activator of transcription (STAT) 1 in regulating CXCL10 expression. Huh7 and HepG2 cells were treated with lysophosphatidylcholine (LPC), the toxic metabolite of the SFA palmitate. In LPC-treated hepatocytes, CXCL10 induction is mediated by a mitogen activated protein kinase (MAPK) signaling cascade consisting of a relay kinase module of MLK3, MKK3/6, and p38. P38 in turn induces STAT1 Ser727 phosphorylation and CXCL10 upregulation in hepatocytes, which is reduced by genetic or pharmacological inhibition of this MAPK signaling cascade. The binding and activity of STAT1 at the CXCL10 gene promoter were identified by chromatin immunoprecipitation and luciferase gene expression assays. Promoter activation was attenuated by MLK3/STAT1 inhibition or by deletion of the consensus STAT1 binding sites within the CXCL10 promoter. In lipotoxic hepatocytes, MLK3 activates a MAPK signaling cascade, resulting in the activating phosphorylation of STAT1, and CXCL10 transcriptional upregulation. Hence, this kinase relay module and/or STAT1 inhibition may serve as a therapeutic target to reduce CXCL10 release, thereby attenuating NASH pathogenesis. J. Cell. Biochem. 118: 3249-3259, 2017. © 2017 Wiley Periodicals, Inc.
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