Knockdown of Hepatic Gonadotropin-Releasing Hormone by Vivo-Morpholino Decreases Liver Fibrosis in Multidrug Resistance Gene 2 Knockout Mice by Down-Regulation of miR-200b

Konstantina Kyritsi, Fanyin Meng, Tianhao Zhou, Nan Wu, Julie Venter, Heather Francis, Lindsey Kennedy, Paolo Onori, Antonio Franchitto, Francesca Bernuzzi, Pietro Invernizzi, Kelly McDaniel, Romina Mancinelli, Domenico Alvaro, Eugenio Gaudio, Gianfranco Alpini, Shannon Glaser

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4 Scopus citations

Abstract

Hepatic fibrosis occurs during the progression of primary sclerosing cholangitis (PSC) and is characterized by accumulation of extracellular matrix proteins. Proliferating cholangiocytes and activated hepatic stellate cells (HSCs) participate in the promotion of liver fibrosis during cholestasis. Gonadotropin-releasing hormone (GnRH) is a trophic peptide hormone synthesized by hypothalamic neurons and the biliary epithelium and exerts its biological effects on cholangiocytes by interaction with the receptor subtype (GnRHR1) expressed by cholangiocytes and HSCs. Previously, we demonstrated that administration of GnRH to normal rats increased intrahepatic biliary mass (IBDM) and hepatic fibrosis. Also, miR-200b is associated with the progression of hepatic fibrosis; however, the role of the GnRH/GnRHR1/miR-200b axis in the development of hepatic fibrosis in PSC is unknown. Herein, using the mouse model of PSC (multidrug resistance gene 2 knockout), the hepatic knockdown of GnRH decreased IBDM and liver fibrosis. In vivo and in vitro administration of GnRH increased the expression of miR-200b and fibrosis markers. The GnRH/GnRHR1 axis and miR-200b were up-regulated in human PSC samples. Cetrorelix, a GnRHR1 antagonist, inhibited the expression of fibrotic genes in vitro and decreased IBDM and hepatic fibrosis in vivo. Inhibition of miR-200b decreased the expression of fibrosis genes in vitro in cholangiocyte and HSC lines. Targeting the GnRH/GnRHR1/miR-200b axis may be key for the management of hepatic fibrosis during the progression of PSC.

Original languageEnglish (US)
Pages (from-to)1551-1565
Number of pages15
JournalAmerican Journal of Pathology
Volume187
Issue number7
DOIs
StatePublished - Jul 1 2017
Externally publishedYes

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Kyritsi, K., Meng, F., Zhou, T., Wu, N., Venter, J., Francis, H., Kennedy, L., Onori, P., Franchitto, A., Bernuzzi, F., Invernizzi, P., McDaniel, K., Mancinelli, R., Alvaro, D., Gaudio, E., Alpini, G., & Glaser, S. (2017). Knockdown of Hepatic Gonadotropin-Releasing Hormone by Vivo-Morpholino Decreases Liver Fibrosis in Multidrug Resistance Gene 2 Knockout Mice by Down-Regulation of miR-200b. American Journal of Pathology, 187(7), 1551-1565. https://doi.org/10.1016/j.ajpath.2017.03.013