DOI: 10.1097/hep.0000000000001149 ISSN: 0270-9139

Platelet-derived mitochondria regulate lipid metabolism in nonalcoholic steatohepatitis via 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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Background & Aims:

Immune system activation along with lipotoxicity due to excessive lipid droplet (LD) accumulation in the liver are key drivers of non-alcoholic steatohepatitis (NASH). Extracellular vesicles (EVs) released by cells that carry biological signals to contribute intercellular communication. But the roles of immune cells-derived EVs in pathogenesis of NASH are unclear.

Approach & Results:

Platelets are abundant in blood. We explored the role of platelet-derived EVs (pEVs) in LD accumulation from 30 patients with non-alcoholic 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 ACC2, and suppressed oxidative phosphorylation system complex II/III/IV activity. These damaged mitochondria could be transferred to hepatocytes via pEVs to increase the number of lipid droplet–bound mitochondria (LDM). An increase in dysfunctional LDM in hepatocytes affects lipid metabolism, resulting in excessive LD accumulation, elevated mitochondrial ROS 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 pEVs components and inhibiting their uptake. Additional experiments are required to confirm this potentiality.

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