Ghrelin reverses ductular reaction and hepatic fibrosis in a rodent model of cholestasis

Abstract The orexigenic peptide ghrelin (Ghr) stimulates hunger signals in the hypothalamus via growth hormone secretagogue receptor (GHS-R1a). Gastric Ghr is synthetized as a preprohormone which is proteolytically cleaved, and acylated by a membrane-bound acyl transferase (MBOAT). Circulating Ghr i...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Anca D. Petrescu, Stephanie Grant, Elaina Williams, Gabriel Frampton, Evan H. Reinhart, Amy Nguyen, Suyeon An, Matthew McMillin, Sharon DeMorrow
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4a3574b8b1a14df69d17b729c93b0c3d
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:4a3574b8b1a14df69d17b729c93b0c3d
record_format	dspace
spelling	oai:doaj.org-article:4a3574b8b1a14df69d17b729c93b0c3d2021-12-02T18:51:13ZGhrelin reverses ductular reaction and hepatic fibrosis in a rodent model of cholestasis10.1038/s41598-020-72681-52045-2322https://doaj.org/article/4a3574b8b1a14df69d17b729c93b0c3d2020-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-72681-5https://doaj.org/toc/2045-2322Abstract The orexigenic peptide ghrelin (Ghr) stimulates hunger signals in the hypothalamus via growth hormone secretagogue receptor (GHS-R1a). Gastric Ghr is synthetized as a preprohormone which is proteolytically cleaved, and acylated by a membrane-bound acyl transferase (MBOAT). Circulating Ghr is reduced in cholestatic injuries, however Ghr’s role in cholestasis is poorly understood. We investigated Ghr’s effects on biliary hyperplasia and hepatic fibrosis in Mdr2-knockout (Mdr2KO) mice, a recognized model of cholestasis. Serum, stomach and liver were collected from Mdr2KO and FVBN control mice treated with Ghr, des-octanoyl-ghrelin (DG) or vehicle. Mdr2KO mice had lower expression of Ghr and MBOAT in the stomach, and lower levels of circulating Ghr compared to WT-controls. Treatment of Mdr2KO mice with Ghr improved plasma transaminases, reduced biliary and fibrosis markers. In the liver, GHS-R1a mRNA was expressed predominantly in cholangiocytes. Ghr but not DG, decreased cell proliferation via AMPK activation in cholangiocytes in vitro. AMPK inhibitors prevented Ghr-induced FOXO1 nuclear translocation and negative regulation of cell proliferation. Ghr treatment reduced ductular reaction and hepatic fibrosis in Mdr2KO mice, regulating cholangiocyte proliferation via GHS-R1a, a G-protein coupled receptor which causes increased intracellular Ca2+ and activation of AMPK and FOXO1, maintaining a low rate of cholangiocyte proliferation.Anca D. PetrescuStephanie GrantElaina WilliamsGabriel FramptonEvan H. ReinhartAmy NguyenSuyeon AnMatthew McMillinSharon DeMorrowNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-19 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anca D. Petrescu Stephanie Grant Elaina Williams Gabriel Frampton Evan H. Reinhart Amy Nguyen Suyeon An Matthew McMillin Sharon DeMorrow Ghrelin reverses ductular reaction and hepatic fibrosis in a rodent model of cholestasis
description	Abstract The orexigenic peptide ghrelin (Ghr) stimulates hunger signals in the hypothalamus via growth hormone secretagogue receptor (GHS-R1a). Gastric Ghr is synthetized as a preprohormone which is proteolytically cleaved, and acylated by a membrane-bound acyl transferase (MBOAT). Circulating Ghr is reduced in cholestatic injuries, however Ghr’s role in cholestasis is poorly understood. We investigated Ghr’s effects on biliary hyperplasia and hepatic fibrosis in Mdr2-knockout (Mdr2KO) mice, a recognized model of cholestasis. Serum, stomach and liver were collected from Mdr2KO and FVBN control mice treated with Ghr, des-octanoyl-ghrelin (DG) or vehicle. Mdr2KO mice had lower expression of Ghr and MBOAT in the stomach, and lower levels of circulating Ghr compared to WT-controls. Treatment of Mdr2KO mice with Ghr improved plasma transaminases, reduced biliary and fibrosis markers. In the liver, GHS-R1a mRNA was expressed predominantly in cholangiocytes. Ghr but not DG, decreased cell proliferation via AMPK activation in cholangiocytes in vitro. AMPK inhibitors prevented Ghr-induced FOXO1 nuclear translocation and negative regulation of cell proliferation. Ghr treatment reduced ductular reaction and hepatic fibrosis in Mdr2KO mice, regulating cholangiocyte proliferation via GHS-R1a, a G-protein coupled receptor which causes increased intracellular Ca2+ and activation of AMPK and FOXO1, maintaining a low rate of cholangiocyte proliferation.
format	article
author	Anca D. Petrescu Stephanie Grant Elaina Williams Gabriel Frampton Evan H. Reinhart Amy Nguyen Suyeon An Matthew McMillin Sharon DeMorrow
author_facet	Anca D. Petrescu Stephanie Grant Elaina Williams Gabriel Frampton Evan H. Reinhart Amy Nguyen Suyeon An Matthew McMillin Sharon DeMorrow
author_sort	Anca D. Petrescu
title	Ghrelin reverses ductular reaction and hepatic fibrosis in a rodent model of cholestasis
title_short	Ghrelin reverses ductular reaction and hepatic fibrosis in a rodent model of cholestasis
title_full	Ghrelin reverses ductular reaction and hepatic fibrosis in a rodent model of cholestasis
title_fullStr	Ghrelin reverses ductular reaction and hepatic fibrosis in a rodent model of cholestasis
title_full_unstemmed	Ghrelin reverses ductular reaction and hepatic fibrosis in a rodent model of cholestasis
title_sort	ghrelin reverses ductular reaction and hepatic fibrosis in a rodent model of cholestasis
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/4a3574b8b1a14df69d17b729c93b0c3d
work_keys_str_mv	AT ancadpetrescu ghrelinreversesductularreactionandhepaticfibrosisinarodentmodelofcholestasis AT stephaniegrant ghrelinreversesductularreactionandhepaticfibrosisinarodentmodelofcholestasis AT elainawilliams ghrelinreversesductularreactionandhepaticfibrosisinarodentmodelofcholestasis AT gabrielframpton ghrelinreversesductularreactionandhepaticfibrosisinarodentmodelofcholestasis AT evanhreinhart ghrelinreversesductularreactionandhepaticfibrosisinarodentmodelofcholestasis AT amynguyen ghrelinreversesductularreactionandhepaticfibrosisinarodentmodelofcholestasis AT suyeonan ghrelinreversesductularreactionandhepaticfibrosisinarodentmodelofcholestasis AT matthewmcmillin ghrelinreversesductularreactionandhepaticfibrosisinarodentmodelofcholestasis AT sharondemorrow ghrelinreversesductularreactionandhepaticfibrosisinarodentmodelofcholestasis
_version_	1718377444728111104

Ghrelin reverses ductular reaction and hepatic fibrosis in a rodent model of cholestasis

Ejemplares similares