ArticleExperimental & molecular medicine2023
Catecholamine induces Kupffer cell apoptosis via growth differentiation factor 15 in alcohol-associated liver disease.
Article in Experimental & molecular medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 19 citations in OpenAlex.
- GDF15 in Liver Fibrosis: Molecular Mechanisms, Immunoregulatory Functions, and Therapeutic Potential.Biomolecules · 2026Review
- Liver-nervous system axis: pathways, dysregulation, and translational perspectives.Journal of neuroinflammation · 2026Review
- Role of myeloid cell transcription factor EB in alcohol-induced liver injury in mice.Liver research (Beijing, China) · 2026Article
- Growth Differentiation Factor 15 (GDF-15) as a modulator of hepatic steatosis and fibrosis: insights from a 6-year retrospective cohort study.Frontiers in medicine · 2026Article
- Liver Innervation in Health and Disease: Neuroimmune-Neurovascular Interface and Future Therapeutic Implications.Biomedicines · 2025Review
- Liver as a key organ for systemic antimicrobial defense.Hepatology communications · 2025Review
- Immunological mechanisms and emerging therapeutic targets in alcohol-associated liver disease.Cellular & molecular immunology · 2025Review
- Kupffer cells are essential for platelet-mediated thrombopoietin generation in the liver.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Binge drinking triggers VGLUT3-mediated glutamate secretion and subsequent hepatic inflammation by activating mGluR5/NOX2 in Kupffer cells.Nature communications · 2025Article
- Advanced Strategies in Enhancing the Hepatoprotective Efficacy of Natural Products: Integrating Nanotechnology, Genomics, and Mechanistic Insights.ACS biomaterials science & engineering · 2025Review
- A systemic effect for liver senescence.Nature cell biology · 2024Article
- Transgenic expression of human cytochrome P450 2E1 in C. elegans and rat PC-12 cells sensitizes to ethanol-induced locomotor and mitochondrial effects.Biochemical and biophysical research communications · 2024Article
- Heme oxygenase 1-mediated ferroptosis in Kupffer cells initiates liver injury during heat stroke.Acta pharmaceutica Sinica. B · 2024Article
- Macrophages as a Source and Target of GDF-15.International journal of molecular sciences · 2024Review
- Exosome-Based Delivery of Super-Repressor IκBα Alleviates Alcohol-Associated Liver Injury in Mice.Pharmaceutics · 2023Article
- Macrophages and the development and progression of non-alcoholic fatty liver disease.Frontiers in immunology · 2023Review
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Authors and funding
21 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chronic alcohol consumption often induces hepatic steatosis but rarely causes severe inflammation in Kupffer cells (KCs) despite the increased hepatic influx of lipopolysaccharide (LPS), suggesting the presence of a veiled tolerance mechanism. In addition to LPS, the liver is affected by several gut-derived neurotransmitters through the portal blood, but the effects of catecholamines on KCs have not been clearly explored in alcohol-associated liver disease (ALD). Hence, we investigated the regulatory roles of catecholamine on inflammatory KCs under chronic alcohol exposure. We discovered that catecholamine levels were significantly elevated in the cecum, portal blood, and liver tissues of chronic ethanol-fed mice. Increased catecholamines induced mitochondrial translocation of cytochrome P450 2E1 in perivenous hepatocytes expressing the β2-adrenergic receptor (ADRB2), leading to the enhanced production of growth differentiation factor 15 (GDF15). Subsequently, GDF15 profoundly increased ADRB2 expression in adjacent inflammatory KCs to facilitate catecholamine/ADRB2-mediated apoptosis. Single-cell RNA sequencing of KCs confirmed the elevated expression of Adrb2 and apoptotic genes after chronic ethanol intake. Genetic ablation of Adrb2 or hepatic Gdf15 robustly decreased the number of apoptotic KCs near perivenous areas, exacerbating alcohol-associated inflammation. Consistently, we found that blood and stool catecholamine levels and perivenous GDF15 expression were increased in patients with early-stage ALD along with an increase in apoptotic KCs. Our findings reveal a novel protective mechanism against ALD, in which the catecholamine/GDF15 axis plays a critical role in KC apoptosis, and identify a unique neuro-metabo-immune axis between the gut and liver that elicits hepatoprotection against alcohol-mediated pathogenic challenges.
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Registered trials
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