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 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.

Predictive and Diagnostic Value of Serum Adipokines in Pregnant Women with Intrahepatic Cholestasis

“…In this study, ghrelin levels were found to be high, while leptin was found to be low, and the antagonistic effect between leptin and ghrelin was preserved. In line with our study results, the ghrelin treatment reduced the ductal reaction and hepatic fibrosis in an experimental study on cholestatic mouse models [ 62 ]. They did not find any literature report examining the relationship of adiponectin and ghrelin with ICP, thus this study may contribute to the literature as the first study in this field.…”

Enteroendocrine Cell Formation Is an Early Event in Pancreatic Tumorigenesis

“…While considered a differentiated cell type in the stomach and intestines, functioning in glucose metabolism (among other roles), GHRL+ cells have also been shown to be a progenitor population in the developing islet ( Wren et al, 2001 ; Tong et al, 2010 ; Arnes et al, 2012 ; Poher et al, 2018 ). Recently, ghrelin was shown to downregulate ductal and fibrotic markers in a genetic model of cholestasis, consistent with an anti-inflammatory role in disease progression ( Petrescu et al, 2020 ). Our data demonstrate that GHRL+ cells are more abundant early in disease progression in both mouse and human, and when coupled with these studies are consistent with a role for ghrelin in mitigating tumorigenesis.…”

p16 INK4A drives nonalcoholic fatty liver disease phenotypes in high fat diet fed mice through biliary E2F1/FOXO1/IGF-1 signaling

“…[10] FOXO1 nuclear translocation is elevated in Mdr2 -/mice, which was reduced by ghrelin. [10] FOXO1 promotes autophagy and lipogenesis through S100A11/HDAC6/FOXO1 signaling in NAFLD [11] and elevates hepatic very LDL production. [12] Although FOXO1 has been studied within the context of hepatocyte function, [3] the role of cholangiocyte FOXO1 and cellular senescence during NAFLD/NASH is not well understood.…”

“…Fork-head box transcription factor O1 (FOXO1) regulates cholangiopathic phenotypes 10 . FOXO1 nuclear translocation is elevated in Mdr2 -/- mice, which was reduced by ghrelin 10 . FOXO1 promotes autophagy and lipogenesis through S100A11/HDAC6/FOXO1 signaling in NAFLD 11 and elevates hepatic very LDL production 12 .…”

“…Fork-head box transcription factor O1 (FOXO1) regulates cholangiopathic phenotypes 10 . FOXO1 nuclear translocation is elevated in Mdr2 -/- mice, which was reduced by ghrelin 10 .…”