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

ATP Binding Cassette Transporter, Subfamily B / genetics Acetyltransferases / metabolism Animals Cell Proliferation / drug effects Cells, Cultured Cholestasis / drug therapy Disease Models, Animal Forkhead Box Protein O1 / metabolism Ghrelin / administration & dosage Liver Cirrhosis / genetics Mice Mice, Knockout Receptors, Ghrelin / genetics Transaminases / blood ATP-Binding Cassette Sub-Family B Member 4

Journal

Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288

Informations de publication

Date de publication:
29 09 2020
Historique:
received: 18 12 2019
accepted: 06 09 2020
entrez: 30 9 2020
pubmed: 1 10 2020
medline: 14 1 2021
Statut: epublish

Résumé

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 Ca

Identifiants

DOI: 10.1038/s41598-020-72681-5 PMID: 32994489 PMC: PMC7525536
pubmed: 32994489
doi: 10.1038/s41598-020-72681-5
pii: 10.1038/s41598-020-72681-5
pmc: PMC7525536
doi:

Substances chimiques

ATP Binding Cassette Transporter, Subfamily B 0
Forkhead Box Protein O1 0
Foxo1 protein, mouse 0
Ghrelin 0
Ghsr1a protein, mouse 0
Receptors, Ghrelin 0
Acetyltransferases EC 2.3.1.-
Transaminases EC 2.6.1.-

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

16024

Subventions

Organisme : BLRD VA
ID : IK2 BX003486
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK112803
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK082435
Pays : United States

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Auteurs

Anca D Petrescu (AD)

Central Texas Veterans Health Care System, Temple, TX, 76504, USA.
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, 78712, USA.

Stephanie Grant (S)

Central Texas Veterans Health Care System, Temple, TX, 76504, USA.
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, 78712, USA.

Elaina Williams (E)

Central Texas Veterans Health Care System, Temple, TX, 76504, USA.
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, 78712, USA.

Gabriel Frampton (G)

Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX, 78701, USA.

Evan H Reinhart (EH)

Department of Internal Medicine, Baylor Scott & White Health, Temple, TX, 76502, USA.

Amy Nguyen (A)

University of Mary Hardin-Baylor, Belton, TX, 76513, USA.

Suyeon An (S)

Central Texas Veterans Health Care System, Temple, TX, 76504, USA.
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, 78712, USA.

Matthew McMillin (M)

Central Texas Veterans Health Care System, Temple, TX, 76504, USA.
Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX, 78701, USA.
ORCID: 0000-0002-5980-0921

Sharon DeMorrow (S)

Central Texas Veterans Health Care System, Temple, TX, 76504, USA. sharon.demorrow@austin.utexas.edu.
Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX, 78712, USA. sharon.demorrow@austin.utexas.edu.
Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX, 78701, USA. sharon.demorrow@austin.utexas.edu.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Pompes ioniques › Transporteurs d'anions › Transporteurs d'anions organiques › Transporteurs d'anions organiques ATP-dépendants › Sous-famille B de transporteurs à cassette liant l'ATP › Ghrelin reverses ductular reaction and hepatic...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Acyltransferases › Acetyltransferases › Ghrelin reverses ductular reaction and hepatic...
questionsmedicales.fr › Eucaryotes › Animaux › Ghrelin reverses ductular reaction and hepatic...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Ghrelin reverses ductular reaction and hepatic...
questionsmedicales.fr › Cellules › Cellules cultivées › Ghrelin reverses ductular reaction and hepatic...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladie des voies biliaires › Maladies des canaux biliaires › Cholestase › Ghrelin reverses ductular reaction and hepatic...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Ghrelin reverses ductular reaction and hepatic...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif hélice ailée › Facteurs de transcription Forkhead › Protéine O1 à motif en tête de fourche › Ghrelin reverses ductular reaction and hepatic...
questionsmedicales.fr › Acides aminés, peptides et protéines › Peptides › Hormones peptidiques › Ghréline › Ghrelin reverses ductular reaction and hepatic...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Fibrose › Cirrhose du foie › Ghrelin reverses ductular reaction and hepatic...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Ghrelin reverses ductular reaction and hepatic...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › Ghrelin reverses ductular reaction and hepatic...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs couplés aux protéines G › Récepteurs à la ghréline › Ghrelin reverses ductular reaction and hepatic...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Nitrogenous group transferases › Transaminases › Ghrelin reverses ductular reaction and hepatic...