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GPR110在代谢功能障碍相关脂肪性肝炎中的表达变化及作用

Expression changes and functional role of GPR110 in metabolic dysfunction-associated steatohepatitis

    摘要
  • 摘要:
    目的 探讨黏附G蛋白偶联受体F1（adhesion G protein-coupled receptor F1，ADGRF1，即G protein-coupled receptor 110，GPR110）在代谢功能障碍相关脂肪性肝炎（metabolic dysfunction-associated steatohepatitis，MASH）肝纤维化中的表达变化及调控作用。
    方法 收集经病理明确诊断为MASH的人类肝组织样本，采用实时荧光定量PCR和免疫组织化学染色检测GPR110表达水平。8周龄雄性C57BL/6小鼠按随机数字表法分为对照＋腺相关病毒（adeno-associated virus，AAV）-绿色荧光蛋白（green fluorescent protein，GFP）组、对照＋AAV-GPR110组、MASH＋AAV-GFP组及MASH＋AAV-GPR110组。利用高脂高糖饮食及低剂量四氯化碳腹腔注射构建MASH小鼠模型，并经尾静脉注射携带GPR110或GFP的AAV。分别于不同建模周期（第4、8、12周）留取肝组织样本。采用蛋白质印迹法检测肝脏内GPR110表达；苏木精-伊红及油红O染色评估肝细胞形态及脂滴含量；F4/80及α-平滑肌肌动蛋白（α-smooth muscle actin，α-SMA）免疫荧光染色评估肝脏组织炎症及纤维化情况；实时荧光定量反转录聚合酶链反应（real-time quantitative reverse transcription polymerase chain reaction，qRT-PCR）检测小鼠肝脏中脂质代谢、炎症及纤维化相关基因的表达水平。
    结果 GPR110在MASH患者肝脏中表达较对照组显著下降（P＜0.05）。MASH＋AAV-GPR110组的体质量、肝脏指数和血脂水平较MASH＋AAV-GFP组显著降低（P＜0.05）；MASH＋AAV-GPR110组肝脏内脂质合成相关基因（SCD1）、脂质摄取相关基因（CD36）、糖异生基因（PEPCK、G-6-Pase）及炎症相关基因（TNF-α、NF-κB及iNOS）表达较MASH＋AAV-GFP组均下降（P＜0.05）。免疫荧光染色结果也证实MASH＋AAV-GPR110组小鼠肝脏组织F4/80及α-SMA阳性区域较MASH＋AAV-GFP组减少（P＜0.05）。
    结论  在MASH病理条件下，增加GPR110表达可以改善肝脏脂质堆积，减轻炎症，延缓肝纤维化进程。

     

    Abstract:
    Objective To investigate expression changes and regulatory roles of adhesion G protein-coupled receptor F1 (ADGRF1/GPR110) in metabolic dysfunction-associated steatohepatitis (MASH)-related hepatic fibrosis.
    Methods Human MASH liver tissues were collected for GPR110 detection via real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. Eight-week-old male C57BL/6 mice were randomly divided into four groups: control＋AAV-GFP group, control＋AAV-GPR110 group, MASH＋AAV-GFP group, and MASH＋AAV-GPR110 group. MASH was induced by high-fat with high-sucrose diet and low-dose CCl4 intraperitoneal injections, with AAV-GPR110/AAV-GFP delivered via tail vein. Liver tissues were harvested at designated intervals (4 w, 8 w, and 12 w). Western blotting measured GPR110 expression; hematoxylin-eosin and oil red O staining assessed histology and lipid content; F4/80 and α-smooth muscle actin (α-SMA) immunofluorescence staining evaluated inflammation and fibrosis; qRT-PCR quantified hepatic expression of lipid metabolism, inflammatory, and fibrotic genes.
    Results GPR110 expression was significantly reduced in livers of MASH patients compared with controls (P＜0.05). MASH＋AAV-GPR110 mice exhibited lower weight, liver index, and serum lipids compared with MASH＋AAV-GFP (P＜0.05). Lipid synthesis-related gene (SCD-1), lipid uptake-related gene (CD36), gluconeogenesis-related genes (PEPCK and G-6-Pase), and inflammation-related genes (TNF-α, NF-κB, and iNOS) in liver were downregulated in MASH＋AAV-GPR110 (P＜0.05). Hepatic F4/80＋ and α-SMA＋ areas decreased in MASH＋AAV-GPR110 (P＜0.05).
    Conclusion GPR110 overexpression ameliorates hepatic lipid accumulation, reduces inflammation, and delays fibrosis in MASH.

     

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