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

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.