Several biomarkers present in circulating extracellular vesicles may help indicate the presence of severe cholestasis-induced liver fibrosis such as in Alagille syndrome (ALGS), according to a new study published in Antioxidants & Redox Signaling.

The micoRNAs (miRNAs) miR192-5p, miR194-5p, miR22-3p, and miR29a-3p were found to be elevated in circulating extracellular vesicles in severe cholestatic mouse models.

These miRNAs were found to be in high concentration in extracellular vesicles collected from bile duct ligation. Drug-induced cholestasis was achieved with 3,5-diethoxycarboncyl-1,4-dihydrocollidine. The miRNAs did not show similar enrichment patterns in the extracellular vesicles of mild cholestatic Mdr2-/- or noncholestatic CCl4-treated mice.


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The authors found that the extracellular vesicles also contained miR122-5p, a miRNA found abundantly in the liver and generally released during hepatocellular injury.

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“Considering the link of the miRNAs under study with extracellular matrix remodeling, we believe that [extracellular vesicle]-associated miR192-5p, miR194-5p, miR22-3p, and miR29a-3p are promising indicators for severe cholestasis-induced liver fibrosis, and if coupled with miR122-5p, a hepatocellular injury-linked miRNA, these could develop into an optimal instrument for early diagnosis of liver fibrosis,” the authors said.

Extracellular vesicle-based mRNAs were also found to be elevated in the mouse models including those for albumin and haptoglobin. Albumin was only found to be present in extracellular vesicles after bile duct ligation despite no significant changes being observed in albumin levels in the liver or whole serum.

“Thus, our data show that the abundance of mRNAs, such as of [haptoglobin] and albumin, in circulating [extracellular vesicles] can be also used as potential biomarkers of cholestatic liver,” the authors concluded.

“The combined use of miRNAs and mRNAs may assist in finding the origin of circulating extracellular vesicles, in detecting in a noninvasive way any pathological changes occurring in the tissues of origin, and in developing assays such as those based on flow cytometry methodology to allow multiple biomarkers detection in a single setting.”

Reference

Fagoonee S, Arigoni M, Manco M, et al. Circulating extracellular vesicles contain liver-derived RNA species as indicators of severe cholestasis-induced early liver fibrosis in mice. Antioxid Redox Signal. 2022;36(7-9):480-504. doi:10.1089/ars.2021.0023