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Hepatic steatosis accelerates vascular endothelial dysfunction by extracellular vesicle-mediated activation of miR-30b-5p/Elovl5 axis

ABSTRACT: Background & Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an independent risk factor for cardiovascular disease (CVD), although the mechanism underlying this association remains unclear. Extracellular vesicles (EVs) are biological nanoparticles that play critical roles in intercellular communication. We aimed to investigate the effects of hepatocyte-derived EVs on vascular endothelial cells in the context of MASLD. Methods: Primary hepatocytes were isolated and exposed under lipotoxic conditions. Human endothelial cells were treated with hepatocyte-derived EVs. Small RNA sequencing was performed to identify candidate microRNAs (miRs) responsible for hepatocyte-endothelial cell crosstalk. The in vivo effect of miR-30b-5p on atherosclerosis was tested in apolipoprotein E knock-out (ApoE-/-) mice. The level of miR-30b-5p in serum EVs was examined in human samples. Results: Treatment with EVs derived from palmitic acid-treated hepatocytes induced endothelial dysfunction in human endothelial cells, characterized by the upregulation of inflammatory cytokines, adhesion molecules, and oxidative stress markers. 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 liver. ELOVL5, a key enzyme in fatty acid elongation, was identified as a direct target of miR-30b-5p. Overexpression of miR-30b-5p or knock-down of Elovl5 inhibited the elongation of polyunsaturated fatty acids (PUFAs), leading to endothelial inflammation, which was rescued by PUFA supplementation. Overexpression of miR-30b-5p accelerated atherogenesis in ApoE-/- mice, whereas downregulation of miR-30b-5p produced the opposite effect. miR-30b-5p levels in human serum-derived EVs were positively correlated with the fatty liver index. Conclusion: Hepatic steatosis accelerates vascular endothelial dysfunction and atherogenesis via EV-mediated activation of the miR-30b-5p/Elovl5 axis. Our findings suggest a novel mechanism explaining the independent relationship between MASLD and CVD.

ORGANISM(S): Mus musculus

PROVIDER: GSE329384 | GEO | 2026/05/28

REPOSITORIES: GEO

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Hepatic steatosis accelerates vascular endothelial dysfunction by extracellular vesicle-mediated activation of miR-30b-5p/Elovl5 axis

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