Intestinal Perfusion of Unacylated Ghrelin Alleviated Metabolic Associated Fatty Liver Disease in Rat via a Central Glucagon-Like Peptide-1 Pathway

Unacylated ghrelin (UAG), the unacylated form of ghrelin, accounts for 80-90% of circulation. Accumulated studies have pointed out that UAG may be used to treat metabolic disorders. This study aimed to investigate the effect of intestinal perfusion of UAG on metabolic associated fatty liver disease (MAFLD) induced by a high-fat diet and its possible mechanism. Neuronal retrograde tracking combined with immunofluorescence, central administration of GLP-1R antagonist, and hepatic vagotomy were performed to reveal its possible mechanism involving a central glucagon-like peptide-1 pathway. The results showed that intestinal perfusion of UAG significantly reduced serum lipids, aminotransferases, and food intake in MAFLD rats. Steatosis and lipid accumulation in the liver were significantly alleviated and lipid metabolism-related enzymes in the liver were regulated. UAG upregulated the expression of GLP-1 receptor (GLP-1R) in the paraventricular nucleus (PVN) and GLP-1 in the nucleus tractus solitarii (NTS), as well as activated GLP-1 neurons in the NTS. Furthermore, GLP-1 fibers projected from NTS to PVN were activated by intestinal perfusion of UAG. However, hepatic vagotomy and GLP-1R antagonist delivered into PVN before intestinal perfusion of UAG partially attenuated its alleviation on MAFLD. In conclusion, intestinal perfusion of UAG showed a therapeutic effect on MAFLD, which might be related to its activating on GLP-1 neuronal pathway from NTS to PVN. The present results provide a new strategy for the treatment of MAFLD.