Extracellular vesicles from steatotic hepatocytes promote endothelial dysfunction and atherogenesis via miR-30b-5p/ELOVL5 axis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as an independent risk factor for cardiovascular disease (CVD), yet the underlying molecular pathways mediating liver-to-vasculature communication remain largely unidentified. Here, we show that extracellular vesicles (EVs) derived from hepatocytes contribute to endothelial dysfunction and atherogenesis. Treatment with EVs derived from palmitic acid (PA)-treated hepatocytes induced inflammation and endothelial dysfunction in human endothelial cells. miR-30b-5p was identified as a candidate cargo, and its elevation was confirmed by qPCR in EVs from PA-treated hepatocytes and Western-diet-induced steatotic livers. ELOVL5 (elongation of very long chain fatty acid protein 5), a key enzyme involved in fatty acid elongation, was identified as a direct target of miR-30b-5p. Overexpression of miR-30b-5p or knockdown of Elovl5 inhibited the elongation of polyunsaturated fatty acids (PUFAs), leading to endothelial inflammation, which was rescued by PUFA supplementation. In vivo, overexpression of miR-30b-5p accelerated atherogenesis, whereas its inhibition ameliorated vascular lesions. miR-30b-5p levels in human serum-derived EVs positively correlated with the early-stage MASLD indices. Our findings identify the EV-derived miR-30b-5p/ELOVL5 axis as a novel mechanistic link between MASLD and CVD. miR-30b-5p may function as both a biomarker and a therapeutic target for early intervention of CVD among patients with MASLD.