ArticleGastroenterology2016
Lipid-Induced Signaling Causes Release of Inflammatory Extracellular Vesicles From Hepatocytes.
Article in Gastroenterology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 322 papers.
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Who cites it
322 citing papers in PubMed, 494 citations in OpenAlex.
- Extracellular Vesicle-Mediated Local and Systemic Communication in Metabolic Diseases.International journal of molecular sciences · 2026Review
- Mitochondrial Distress Signals at the Heart-Liver Interface: Molecular Links Between MASLD and Heart Failure.International journal of molecular sciences · 2026Review
- HFpEF and MASLD: converging mechanisms and clinical implications.Nature reviews. Cardiology · 2026Review
- Liver Macrophages in the Pathogenesis of Viral Hepatitis.Current issues in molecular biology · 2026Review
- From steatosis to metastasis: microenvironmental reprogramming of the liver in metabolic dysfunction-associated steatotic liver disease.Clinical and molecular hepatology · 2026Review
- Reprogramming macrophages to treat liver diseases.Hepatology (Baltimore, Md.) · 2026Review
- Review
- Dual GIP/GLP-1 receptor agonist tirzepatide ameliorates hepatic steatosis and inflammatory responses in a MASLD mouse model associated with the CCL2/CCR2 axis.BMC gastroenterology · 2026Article
- An LSEC-focused computational drug repurposing platform for liver fibrosis: Identification of vorinostat and other LSEC-protective candidates.bioRxiv : the preprint server for biology · 2026Article
- Burn-associated metabolic dysfunction: could extracellular vesicles play a role?Clinical science (London, England : 1979) · 2026Review
- ROCK signaling at the crossroads of redox stress, mitochondrial dynamics, and metabolic disease.Redox biology · 2026Review
- Serum Proteomics of Insulin Resistance Disorders Distinguish MASLD From Lipodystrophy and Insulin Receptor Defects.The Journal of clinical endocrinology and metabolism · 2026Article
- Circulating Liver-Derived and CD36Journal of extracellular vesicles · 2026Article
- Diagnostic and prognostic significance of circulating extracellular vesicles in gastrointestinal cancers.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Multi-lineage hepatic organoids reveal toxic exosome mediated indirect hepatotoxicity.Nature communications · 2026Article
- Extracellular Vesicles in Liver Fibrosis: Pathogenic Messengers, Diagnostic Biomarkers, and Therapeutic Nanovectors.Pharmaceutics · 2026Review
- Hepatocyte-hepatic stellate cell interactions in liver fibrosis: Mechanisms and therapeutic implications.Hepatology communications · 2026Review
- Orphan drug uttroside B impedes MASH progression and HCC development in experimental models.JHEP reports : innovation in hepatology · 2026Article
- Extracellular Vesicles: Orchestrators of Intrahepatic and Systemic Crosstalk in Metabolic Dysfunction-Associated Steatotic Liver Disease.Pharmaceutics · 2026Review
- Interferon Regulatory Factors in Alcohol-Associated Liver Disease: Cell-Type Programs, Danger Signaling, and Therapeutic Opportunities.Current issues in molecular biology · 2026Review
262 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
BACKGROUND &
aimsHepatocyte cellular dysfunction and death induced by lipids and macrophage-associated inflammation are characteristics of nonalcoholic steatohepatitis (NASH). The fatty acid palmitate can activate death receptor 5 (DR5) on hepatocytes, leading to their death, but little is known about how this process contributes to macrophage-associated inflammation. We investigated whether lipid-induced DR5 signaling results in the release of extracellular vesicles (EVs) from hepatocytes, and whether these can induce an inflammatory macrophage phenotype.
methodsPrimary mouse and human hepatocytes and Huh7 cells were incubated with palmitate, its metabolite lysophosphatidylcholine, or diluent (control). The released EV were isolated, characterized, quantified, and applied to macrophages. C57BL/6 mice were placed on chow or a diet high in fat, fructose, and cholesterol to induce NASH. Some mice also were given the ROCK1 inhibitor fasudil; 2 weeks later, serum EVs were isolated and characterized by immunoblot and nanoparticle-tracking analyses. Livers were collected and analyzed by histology, immunohistochemistry, and quantitative polymerase chain reaction.
resultsIncubation of primary hepatocytes and Huh7 cells with palmitate or lysophosphatidylcholine increased their release of EVs, compared with control cells. This release was reduced by inactivating mediators of the DR5 signaling pathway or rho-associated, coiled-coil-containing protein kinase 1 (ROCK1) inhibition. Hepatocyte-derived EVs contained tumor necrosis factor-related apoptosis-inducing ligand and induced expression of interleukin 1β and interleukin 6 messenger RNAs in mouse bone marrow-derived macrophages. Activation of macrophages required DR5 and receptor-interacting protein kinase 1. Administration of the ROCK1 inhibitor fasudil to mice with NASH reduced serum levels of EVs; this reduction was associated with decreased liver injury, inflammation, and fibrosis.
conclusionsLipids, which stimulate DR5, induce release of hepatocyte EVs, which activate an inflammatory phenotype in macrophages. Strategies to inhibit ROCK1-dependent release of EVs by hepatocytes might be developed for the treatment of patients with NASH.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.