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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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

Fingerprint

MDR Genes
Morpholinos
Gene Knockout Techniques
Knockout Mice
Gonadotropin-Releasing Hormone
Liver Cirrhosis
Fibrosis
Down-Regulation
Sclerosing Cholangitis
Liver
Hepatic Stellate Cells
Gene Expression
Peptide Hormones
Extracellular Matrix Proteins
Cholestasis
Epithelium
Neurons
Cell Line

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

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

In: American Journal of Pathology, Vol. 187, No. 7, 01.07.2017, p. 1551-1565.

Research output: Contribution to journalArticle

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, vol. 187, no. 7, pp. 1551-1565. https://doi.org/10.1016/j.ajpath.2017.03.013
Kyritsi, Konstantina ; Meng, Fanyin ; Zhou, Tianhao ; Wu, Nan ; Venter, Julie ; Francis, Heather ; Kennedy, Lindsey ; Onori, Paolo ; Franchitto, Antonio ; Bernuzzi, Francesca ; Invernizzi, Pietro ; McDaniel, Kelly ; Mancinelli, Romina ; Alvaro, Domenico ; Gaudio, Eugenio ; Alpini, Gianfranco ; Glaser, Shannon. / 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. In: American Journal of Pathology. 2017 ; Vol. 187, No. 7. pp. 1551-1565.
@article{8f58dd56ffad424fb054b301d6f18d94,
title = "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",
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.",
author = "Konstantina Kyritsi and Fanyin Meng and Tianhao Zhou and Nan Wu and Julie Venter and Heather Francis and Lindsey Kennedy and Paolo Onori and Antonio Franchitto and Francesca Bernuzzi and Pietro Invernizzi and Kelly McDaniel and Romina Mancinelli and Domenico Alvaro and Eugenio Gaudio and Gianfranco Alpini and Shannon Glaser",
year = "2017",
month = "7",
day = "1",
doi = "10.1016/j.ajpath.2017.03.013",
language = "English (US)",
volume = "187",
pages = "1551--1565",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "7",

}

TY - JOUR

T1 - 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

AU - Kyritsi, Konstantina

AU - Meng, Fanyin

AU - Zhou, Tianhao

AU - Wu, Nan

AU - Venter, Julie

AU - Francis, Heather

AU - Kennedy, Lindsey

AU - Onori, Paolo

AU - Franchitto, Antonio

AU - Bernuzzi, Francesca

AU - Invernizzi, Pietro

AU - McDaniel, Kelly

AU - Mancinelli, Romina

AU - Alvaro, Domenico

AU - Gaudio, Eugenio

AU - Alpini, Gianfranco

AU - Glaser, Shannon

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85020840325&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020840325&partnerID=8YFLogxK

U2 - 10.1016/j.ajpath.2017.03.013

DO - 10.1016/j.ajpath.2017.03.013

M3 - Article

C2 - 28502477

AN - SCOPUS:85020840325

VL - 187

SP - 1551

EP - 1565

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 7

ER -