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

The American Journal of Pathology
Konstantina KyritsiS S Glaser

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 t...Continue Reading

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Citations

Jun 27, 2017·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Keisaku SatoGianfranco Alpini
Feb 7, 2019·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Kelly McDanielFanyin Meng
Feb 16, 2020·Journal of Pineal Research·Keisaku SatoGianfranco Alpini
Sep 12, 2019·American Journal of Physiology. Gastrointestinal and Liver Physiology·Leonardo BaiocchiGianfranco Alpini
Aug 8, 2020·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Konstantina KyritsiHeather Francis
Mar 7, 2020·The American Journal of Pathology·Lindsey KennedyHeather Francis

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