Cholangiocyte-Derived Exosomal Long Noncoding RNA H19 Promotes Cholestatic Liver Injury in Mouse and Humans

Abstract

Cholestatic liver injury is an important clinical problem with limited understanding of disease pathologies. Exosomes are small extracellular vesicles released by a variety of cells, including cholangiocytes. Exosome-mediated cell-cell communication can modulate various cellular functions by transferring a variety of intracellular components to target cells. Our recent studies indicate that the long noncoding RNA (lncRNA), H19, is mainly expressed in cholangiocytes, and its aberrant expression is associated with significant down-regulation of small heterodimer partner (SHP) in hepatocytes and cholestatic liver injury in multidrug resistance 2 knockout (Mdr2−/−) mice. However, how cholangiocyte-derived H19 suppresses SHP in hepatocytes remains unknown. Here, we report that cholangiocyte-derived exosomes mediate transfer of H19 into hepatocytes and promote cholestatic injury. Hepatic H19 level is correlated with severity of cholestatic injury in both fibrotic mouse models, including Mdr2−/− mice, a well-characterized model of primary sclerosing cholangitis (PSC), or CCl4-induced cholestatic liver injury mouse models, and human PSC patients. Moreover, serum exosomal-H19 level is gradually up-regulated during disease progression in Mdr2−/− mice and patients with cirrhosis. H19-carrying exosomes from the primary cholangiocytes of wild-type (WT) mice suppress SHP expression in hepatocytes, but not the exosomes from the cholangiocytes of H19−/− mice. Furthermore, overexpression of H19 significantly suppressed SHP expression at both transcriptional and posttranscriptional levels. Importantly, transplant of H19-carrying serum exosomes of old fibrotic Mdr2−/− mice significantly promoted liver fibrosis (LF) in young Mdr2−/− mice. Conclusion: Cholangiocyte-derived exosomal-H19 plays a critical role in cholestatic liver injury. Serum exosomal H19 represents a noninvasive biomarker and potential therapeutic target for cholestatic diseases.

Department(s)

Chemical and Biochemical Engineering

Keywords and Phrases

estrogen; protein tyrosine phosphatase SHP; RNA H19; taurocholic acid; cell receptor; H19 long non-coding RNA; long untranslated RNA; nuclear receptor subfamily 0, group B, member 2, animal cell; animal experiment; animal model; animal tissue; Article; blood level; carbon tetrachloride-induced liver injury; cholangiocyte; controlled study; disease severity; exosome; female; gene overexpression; human; human tissue; in vivo study; liver cell; liver cirrhosis; liver fibrosis; male; mouse; nonhuman; pathogenesis; primary sclerosing cholangitis; priority journal; protein expression; RNA transport; upregulation; animal; bile duct; cholestasis; exosome; genetics; knockout mouse; liver; metabolism; pathology; sclerosing cholangitis, Animals; Bile Ducts; Cholangitis, Sclerosing; Cholestasis; Exosomes; Female; Hepatocytes; Humans; Liver; Male; Mice; Mice, Knockout; Receptors, Cytoplasmic and Nuclear; RNA, Long Noncoding

International Standard Serial Number (ISSN)

0270-9139; 1527-3350

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2018 American Association for the Study of Liver Diseases, All rights reserved.

Publication Date

01 Aug 2018

PubMed ID

29425397

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