Miao Rong-Rong, Tan Ming-Yong, Shao Han-Bing, Sun Zhi-Meng, Zhan Sheng, Liang Wei-Shi, Liu Xiao-Hui, Li Ke-Qin, Cheng Yu-Yao, Wu Xin-Feng, Xu Rui, Cui Shu-Xiang, Hai Yong, Qu Xian-Jun
Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.
Department of Pharmacy, The Affiliated Children's Hospital of Xiangya School of Medicine, Central South University (Hunan Children's Hospital), Changsha, 410007, China.
Cell Commun Signal. 2025 May 25;23(1):240. doi: 10.1186/s12964-025-02249-1.
Conjugated bile acids (CBAs) induced metabolic dysfunction-associated steatotic liver disease (MASLD) through activating sphingosine-1-phosphate receptor 2 (S1PR2). However, the precise mechanisms have not been fully understood.
We established a link between CBAs and MASLD in IBD patients with high SphK2 and Villin-SphK2TG mice. Villin-SphK2TG mice were fed high-fat diet (HFD) for inducing MASLD. Gut microbiota composition was analyzed by 16 S rDNA Amplicon sequencing assay. We performed the UPLC/TQMS based targeted metabolomics assay to analyze the compositions of BAs in liver, serum and feces. In vitro assays, hepatocytes transfected with N-terminal truncated-S1PR2 analyzed the dynamics of S1PR2 stimulated by CBAs. PPARα function was assayed by analyzing the DNA-protein interactions by using Electrophoretic mobility shift assay (EMSA).
The IBD patients with high colonocyte SphK2 conferred the development of MASLD. Feeding high-fat diet, Villin-SphK2TG mice developed MASLD more severely than WT mice. Analysis of gut microbiota showed that colonic SphK2 shaped microbiota by reducing the BSH-producing bacteria, thus leading to the accumulation of CBAs in liver via the gut-liver axis. CBAs induced nuclear translocation of S1PR2 through cleavage the N-terminal sequences of Ala-Ser-Ala-Phe-Iso in hepatocytes. Cleaved S1PR2 (S1PR2') was thus translocated into the nucleus to bind with PPARα, thereby interdicting the function of PPARα in regulating the genes involved in lipid catabolism. S1PR2 antagonist JTE-013 blocked the CBAs-induced nuclear translocation of S1PR2 and S1PR2 is thus identified as a potential therapeutic target for MASLD treatment.
CBAs promoted MASLD through inducing S1PR2 translocation into the nucleus, where it bound PPARα to interdict the function of PPARα in regulating genes involved in lipid catabolism.
共轭胆汁酸（CBAs）通过激活鞘氨醇-1-磷酸受体2（S1PR2）诱导代谢功能障碍相关脂肪性肝病（MASLD）。然而，确切机制尚未完全阐明。
我们在高SphK2的炎症性肠病（IBD）患者和Villin-SphK2转基因小鼠中建立了CBAs与MASLD之间的联系。给Villin-SphK2转基因小鼠喂食高脂饮食（HFD）以诱导MASLD。通过16S rDNA扩增子测序分析肠道微生物群组成。我们进行了基于超高效液相色谱/串联四极杆质谱（UPLC/TQMS）的靶向代谢组学分析，以分析肝脏、血清和粪便中胆汁酸的组成。在体外实验中，用N端截短的S1PR2转染的肝细胞分析了CBAs刺激S1PR2的动力学。通过电泳迁移率变动分析（EMSA）分析DNA-蛋白质相互作用来检测过氧化物酶体增殖物激活受体α（PPARα）的功能。
结肠上皮细胞SphK2高表达的IBD患者易发生MASLD。喂食高脂饮食时，Villin-SphK2转基因小鼠比野生型小鼠更易发生严重的MASLD。肠道微生物群分析表明，结肠SphK2通过减少产胆盐水解酶（BSH）的细菌来塑造微生物群，从而通过肠-肝轴导致肝脏中CBAs的积累。CBAs通过切割肝细胞中Ala-Ser-Ala-Phe-Iso的N端序列诱导SPR2的核转位。切割后的S1PR2（S1PR2'）因此转位到细胞核中与PPARα结合，从而阻断PPARα在调节参与脂质分解代谢的基因中的功能。S1PR2拮抗剂JTE-013阻断了CBAs诱导的S1PR2核转位，因此S1PR2被确定为MASLD治疗的潜在靶点。
CBAs通过诱导S1PR2转位到细胞核中促进MASLD，在细胞核中它与PPARα结合，从而阻断PPARα在调节参与脂质分解代谢的基因中的功能。
