Hepatocytes derived extracellular vesicles from high-fat diet induced obese mice modulate genes expression and proliferation of islet β cells

Abstract

Liver secretes proliferative factors participating compensatory hyperplasia of islets during obesity and insulin resistance. Extracellular vesicles (EVs) mediate intercellular communication by delivering inner factors to recipient cells. This study explored the biological effects of hepatocellular EVs on islet β cells during obesity. Compared with standard chow diet (CD), hepatocellular EVs derived from high-fat diet (HFD) induced obese mice promoted proliferation of β cell line-MIN6 cells, but didn't influence their insulin secretion. Microarray analysis found 13 miRNAs with significantly differential expression in hepatocellular EVs between HFD with CD group. Meanwhile, RNA-sequencing detected 80 genes with significantly differential expression in MIN6 cells treated with HFD and CD hepatocellular EVs respectively. Six miRNAs and 11 potential target genes were pre-screened by synthesizing TargetScan prediction and RNA-sequencing results. After miRNA mimic transfection and testing the expressions of target genes and cell vitality, miR-7218-5p was verified to affect MIN6 cell proliferation through targeting CD74 gene. SiRNA transfection and dual luciferase reporter assay further confirmed the binding and regulation of miRNA-7218-5p on CD74. These findings suggest HFD induced obesity could change miRNA profiles in hepatocellular EVs, which modulate expression of multiple genes and proliferation of MIN6 cells and maybe mediate compensatory hyperplasia of islets.

Keywords: Extracellular vesicles; Islets; Liver; miRNA; β cell.