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PubMed · 39509377

Platelet-derived mitochondria regulate lipid metabolism in nonalcoholic steatohepatitis through extracellular vesicles.

Tsai-Ling Liao·Der-Yuan Chen·Shie-Liang Hsieh·Ying-Ying Yang·Yi-Ming Chen·Kuo-Tung Tang·Chung-Hsin Chang·Sheng-Shun Yang
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Abstract

BACKGROUND AND AIMS: Immune system activation, along with lipotoxicity due to excessive lipid droplet (LD) accumulation in the liver, are key drivers of NASH. Extracellular vesicles (EVs) released by cells that carry biological signals contribute to intercellular communication. However, the roles of immune cell-derived EVs in the pathogenesis of NASH are unclear. APPROACH AND RESULTS: Platelets are abundant in blood. We explored the role of platelet-derived EVs (pEVs) in LD accumulation from 30 patients with nonalcoholic fatty liver disease of different severity as well as 20 healthy subjects, a rat model, and an in vitro cell-based assay. There was increased platelet activation, accompanied by pEVs release, in NASH patients/rat model, and palmitate-treated cells. The mitochondria in the platelets and pEVs from NASH patients/rats were increased but dysfunctional, including a reduction in fatty acid β-oxidation, inactivated acetyl-CoA carboxylase 2, and suppressed oxidative phosphorylation system complex II/III/IV activity. These damaged mitochondria could be transferred to hepatocytes through pEVs to increase the number of lipid droplet-bound mitochondria. An increase in dysfunctional lipid droplet-bound mitochondria in hepatocytes affects lipid metabolism, resulting in excessive LD accumulation, elevated mitochondrial reactive oxygen species production, and apoptosis. CONCLUSIONS: We offer a novel molecular mechanism that connects platelets, pEVs, and excessive LD accumulation to the development of NASH. Our results suggest that NASH progression may be alleviated by specifically inhibiting the production and release of pEVs, or by targeting pEV components and inhibiting their uptake. Additional experiments are required to confirm this potentiality.

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Non-alcoholic Fatty Liver DiseaseExtracellular VesiclesHumansAnimalsRatsLipid MetabolismMaleBlood PlateletsMitochondriaMiddle AgedFemaleHepatocytesLipid DropletsDisease Models, AnimalAdultPlatelet ActivationNAFLDimmune cellsintercellular communicationlipid droplet–bound mitochondrialipotoxic fatty acidsJournal ArticleResearch Support, Non-U.S. Gov't

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Tsai-Ling Liao, Der-Yuan Chen, Shie-Liang Hsieh, Ying-Ying Yang, Yi-Ming Chen, Kuo-Tung Tang, Chung-Hsin Chang, Sheng-Shun Yang. 2024-11-07. Platelet-derived mitochondria regulate lipid metabolism in nonalcoholic steatohepatitis through extracellular vesicles.. https://doi.org/10.1097/hep.0000000000001149

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