Hepatic LGR4 aggravates cholestasis-induced liver injury in mice.

IF 3.9 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Yuan Gao, Wenbo Zhai, Lijun Sun, Xueqian Du, Xianfeng Wang, Michael W Mulholland, Yue Yin, Weizhen Zhang
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引用次数: 0

Abstract

Current therapy for hepatic injury induced by the accumulation of bile acids 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 downregulated. 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 acids 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 protein kinase B (AKT) induced by BDL. Recombinant Rspo1 and Rspo3 potentiated the taurocholic acid (TCA)-induced upregulation 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 R-spondins (Rspos)-LGR4 signaling in hepatocytes aggravates the cholestatic liver injury by potentiating the production of bile acids in a S1PR2-AKT-dependent manner.NEW & NOTEWORTHY Deficiency of LGR4 in hepatocytes alleviates BDL-induced liver injury. LGR4 in macrophages demonstrates no effect on BDL-induced liver injury. Rspos-LGR4 increases bile acid synthesis and transport via potentiating S1PR2-AKT signaling in hepatocytes.

肝脏 LGR4 会加重胆汁淤积引起的小鼠肝损伤。
目前针对胆汁酸蓄积引起的肝损伤的治疗方法有限。富亮氨酸重复 G 蛋白偶联受体 4(LGR4),又称 GPR48,对细胞保护和细胞增殖至关重要。在这里,我们报告了 LGR4 在胆汁淤积性肝损伤中的一种新功能。在胆管结扎(BDL)诱导的肝损伤模型中,肝脏 LGR4 的表达显著下调。肝细胞中 LGR4 的缺失(Lgr4LKO)明显减轻了 BDL 诱导的肝损伤,肝损伤表现为肝坏死、肝纤维化、循环肝酶和总胆红素。这些小鼠血浆和肝脏中的总胆汁酸水平明显降低。然而,巨噬细胞中 LGR4 的缺乏(Lyz2-Lgr4MKO)对 BDL 诱导的肝损伤没有明显影响。肝细胞中 LGR4 的缺乏会明显减轻 S1PR2 和 BDL 诱导的 AKT 磷酸化。重组 Rspo1 和 Rspo3 可增强 TCA 诱导的肝细胞 S1PR2 上调和 AKT 磷酸化。通过特异性 AKT 或 S1PR2 抑制剂抑制 S1PR2-AKT 信号传导可阻断 Rspo1/3 在肝细胞中诱导的胆汁酸分泌增加。我们的研究表明,肝细胞中的 Rspo-LGR4 信号通过 S1PR2-AKT 依赖性方式促进胆汁酸分泌,从而加重胆汁淤积性肝损伤。
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来源期刊
CiteScore
9.40
自引率
2.20%
发文量
104
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Gastrointestinal and Liver Physiology publishes original articles pertaining to all aspects of research involving normal or abnormal function of the gastrointestinal tract, hepatobiliary system, and pancreas. Authors are encouraged to submit manuscripts dealing with growth and development, digestion, secretion, absorption, metabolism, and motility relative to these organs, as well as research reports dealing with immune and inflammatory processes and with neural, endocrine, and circulatory control mechanisms that affect these organs.
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