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

Tytuł:: Ghrelin reverses ductular reaction and hepatic fibrosis in a rodent model of cholestasis.
Autorzy:: 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.
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.
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.
Frampton G; Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX, 78701, USA.
Reinhart EH; Department of Internal Medicine, Baylor Scott & White Health, Temple, TX, 76502, USA.
Nguyen A; University of Mary Hardin-Baylor, Belton, TX, 76513, USA.
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.
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.
DeMorrow 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. .; Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX, 78701, USA. .
Źródło:: Scientific reports [Sci Rep] 2020 Sep 29; Vol. 10 (1), pp. 16024. Date of Electronic Publication: 2020 Sep 29.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.
Język:: English
Imprint Name(s):: Original Publication: London : Nature Publishing Group, copyright 2011-
MeSH Terms:: Cholestasis/*drug therapy
Ghrelin/*administration & dosage
Liver Cirrhosis/*prevention & control
Receptors, Ghrelin/*genetics
ATP Binding Cassette Transporter, Subfamily B/genetics ; Acetyltransferases/metabolism ; Animals ; Cell Proliferation/drug effects ; Cells, Cultured ; Cholestasis/genetics ; Cholestasis/metabolism ; Disease Models, Animal ; Forkhead Box Protein O1/metabolism ; Ghrelin/metabolism ; Ghrelin/pharmacology ; Liver Cirrhosis/genetics ; Liver Cirrhosis/metabolism ; Mice ; Mice, Knockout ; Transaminases/blood ; ATP-Binding Cassette Sub-Family B Member 4
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Grant Information:: IK2 BX003486 United States BX BLRD VA; R01 DK112803 United States DK NIDDK NIH HHS; R01 DK082435 United States DK NIDDK NIH HHS
Substance Nomenclature:: 0 (ATP Binding Cassette Transporter, Subfamily B)
0 (Forkhead Box Protein O1)
0 (Foxo1 protein, mouse)
0 (Ghrelin)
0 (Ghsr1a protein, mouse)
0 (Receptors, Ghrelin)
EC 2.3.1.- (Acetyltransferases)
EC 2.6.1.- (Transaminases)
Entry Date(s):: Date Created: 20200930 Date Completed: 20210113 Latest Revision: 20231213
Update Code:: 20240105
PubMed Central ID:: PMC7525536
DOI:: 10.1038/s41598-020-72681-5
PMID:: 32994489
: Czasopismo naukowe

Pełny tekst

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 2+ and activation of AMPK and FOXO1, maintaining a low rate of cholangiocyte proliferation.

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