Hepatic LGR4 aggravates cholestasis-induced liver injury in mice

Am J Physiol Gastrointest Liver Physiol. 2024 Mar 5. doi: 10.1152/ajpgi.00127.2023. Online ahead of print.ABSTRACTCurrent therapy for hepatic injury induced by accumulation of bile acid is limited. Leucine-rich repeat G-protein-coupled receptor 4 (LGR4), also known as GPR48, is critical for cytoprotection and cell proliferation. Here, we reported a novel function for the LGR4 in cholestatic liver injury. In the bile duct ligation (BDL) induced liver injury model, hepatic LGR4 expression was significantly down-regulated. Deficiency of LGR4 in hepatocytes (Lgr4LKO) notably decreased BDL-induced liver injury measured by hepatic necrosis, fibrosis, and circulating liver enzymes and total bilirubin. Levels of total bile acid in plasma and liver were markedly reduced in these mice. However, deficiency of LGR4 in macrophages (Lyz2-Lgr4MKO) demonstrated no significant effect on liver injury induced by BDL. Deficiency of LGR4 in hepatocytes significantly attenuated S1PR2 and the phosphorylation of AKT induced by BDL. Recombinant Rspo1 and Rspo3 potentiated the TCA-induced up-regulation in S1PR2 and phosphorylation of AKT in hepatocytes. Inhibition of S1PR2-AKT signaling by specific AKT or S1PR2 inhibitors blocked the increase of bile acid secretion induced by Rspo1/3 in hepatocytes. Our studies indicate that the Rspo-LGR4 signaling in hepatocytes aggravates the cholestatic liver injury by potentiating the production of bile acid in a S1PR2-AKT-dependent manner.PMID:38440827 | DOI:10.1...
Source: Am J Physiol Gastroi... - Category: Gastroenterology Authors: Source Type: research