Suppression of Intestinal Mucosal Apoptosis by Ghrelin in Fasting Rats

Abstract

Ghrelin is mainly produced in the stomach and has several physiologic functions. The aim of this study was to investigate whether ghrelin regulates apoptosis in the small intestinal mucosa of fasting rats. Intestinal mucosal apoptosis was evaluated as the percentage of fragmented DNA, villus height, and terminal deoxynucleotidyl transferase-mediated dUDP-biotin nick end-labeling (TUNEL) staining and by Western blot analysis of caspase-3 in 48-hr fasting rats. Crypt cell proliferation was evaluated by counting the number of 5-bromo-2-deoxyuridine (BrdU) positive cells. Ghrelin was administered intraperitoneally at dosages of 2.5, 25, and 250 microg/kg per 48 hrs by continuous infusion via an Alzet micro-osmotic pump or injections at 12-hr intervals. Ghrelin was also infused in rats that underwent truncal vagotomy. The lowest dosage of ghrelin (2.5 microg/kg per 48 hrs) was administered into the third cerebroventricle. Ghrelin treatment attenuated the percentage of fragmented DNA in the small intestinal mucosa in 48-hr fasting rats in a dose-dependent manner. Continuous infusion of ghrelin and injections of ghrelin at 12-hr intervals suppressed intestinal apoptosis almost equally. This effect on apoptosis was not attenuated by truncal vagotomy. Cerebroventricular infusion of ghrelin also attenuated intestinal apoptosis. The antiapoptotic effect of ghrelin was confirmed by decreased TUNEL staining, recovery of the villus height, and decreased expression of caspase-3. BrdU uptake indicated that ghrelin enhanced cell proliferation in the intestinal crypt. Taken together, these data indicate that ghrelin enhanced intestinal growth with the suppression of small intestinal mucosal apoptosis in 48-hr fasting rats, suggesting that ghrelin controls intestinal function through the regulation of intestinal apoptosis.

Ghrelin inhibits sodium metabisulfite induced oxidative stress and apoptosis in rat gastric mucosa

“…This is the very first study reporting that ghrelin treatment decreases the number apoptotic cells, PAR and caspase-3 expressions while increasing Ki67 expression in gastric mucosa exposed to Na 2 S 2 O 5 . Similar to our findings Park et al have demonstrat ed that ghrelin enhances the proliferation of crypt cells in the small intestine and attenuates intestinal apoptosis (Park et al, 2008 ). Moreover, several reports suggested that ghrelin decreases TUNEL positive rate and caspase 3 levels in endothelial cells, spinal cord and neurons (Lopez et al, 2012;Zhang et al, 2012;Zhao et al, 2007 ).…”

Ghrelin, des-acyl ghrelin and obestatin: Three pieces of the same puzzle

“…The protective effect has also been demonstrated in experimental colitis [57]. A recent study showed that, both intraperitoneally and centrally administered, ghrelin suppresses mucosal intestinal apoptosis in fasting rats [113].…”

Expression, regulation and biological actions of growth hormone (GH) and ghrelin in the immune system

“…Ghrelin protected hypothalamic neurons from oxygen glucose deprivation insult by inhibiting reactive oxygen species generation and stabilizing mitochondrial transmembrane potential [160]. The anti-apoptotic effect of ghrelin has been reported in several other cells such as pancreatic b-cells [156], intestinal epithelial cells [161], adipocytes [162], cardiomyocytes and endothelial cells [163]. The anti-apoptotic effect of ghrelin seems to be mediated via phosphatidyl inositol 3-kinase (PI3K) activation and glycogen synthase kinase-3b (GSK-3b) suppression, and stabilization of b catenin [164].…”