Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
Department of Gastroenterology, School of Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University, Hangzhou, 310003, China.
Hepatol Int. 2022 Oct;16(5):1064-1074. doi: 10.1007/s12072-022-10371-2. Epub 2022 Aug 25.
Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide. The important role of urid acid (UA) in MAFLD has been widely investigated. Our previous studies unveiled the elevation of serum UA levels independently predicts an increased risk of incident MAFLD. However, the role of intrahepatic UA in MAFLD has not been investigated yet. Glucose transporter 9 (GLUT9) is a key transporter that mediates the uptake of UA in hepatocytes.
In this study, we first explored the clinical association between GLUT9 polymorphism and MAFLD. Blood samples of 247 male Chinese (127 were MAFLD patients) were collected and tested for the blood UA levels and genotype of the single nucleotide polymorphism (SNP) of GLUT9 (rs1014290). Next, Glut9 hepatic-specific knockout mice (Glut9) were generated to investigate the role of hepatic GLUT9 in MAFLD in male mice.
We found that the GA/AA genotypes (rs1014290) were associated with elevated serum UA levels in MAFLD patients. Meanwhile, we found that Glut9 mice displayed lower intrahepatic UA levels, down-regulated lipogenesis genes expressions, and attenuated MAFLD symptoms after 12 weeks of high-fat diet feeding, compared with Glut9 littermates. However, Glut9 mice and wild-type littermates showed no significant difference on hepatic fatty acid oxidation or inflammation.
Our results suggested that GLUT9 polymorphism was significantly associated with MAFLD, and hepatic-specific knockout of Glut9 significantly decreased intrahepatic contents and ameliorated diet-induced MAFLD in mice.
代谢相关脂肪性肝病（MAFLD）是全球最常见的慢性肝病。尿酸（UA）在 MAFLD 中的重要作用已被广泛研究。我们之前的研究揭示了血清 UA 水平的升高独立预测 MAFLD 发病风险增加。然而，肝内 UA 在 MAFLD 中的作用尚未被研究。葡萄糖转运蛋白 9（GLUT9）是一种关键转运蛋白，介导肝细胞摄取 UA。
本研究首先探讨了 GLUT9 多态性与 MAFLD 的临床相关性。收集了 247 名男性中国人（127 名为 MAFLD 患者）的血液样本，检测血液 UA 水平和 GLUT9 单核苷酸多态性（SNP）（rs1014290）的基因型。接下来，生成了 Glut9 肝特异性敲除小鼠（Glut9），以研究雄性小鼠肝 GLUT9 在 MAFLD 中的作用。
我们发现 rs1014290 基因型与 MAFLD 患者血清 UA 水平升高相关。同时，我们发现 Glut9 小鼠的肝内 UA 水平较低，脂生成基因表达下调，并在高脂肪饮食喂养 12 周后减轻 MAFLD 症状，而 Glut9 同窝仔鼠则没有。然而，Glut9 小鼠和野生型同窝仔鼠的肝脂肪酸氧化或炎症无明显差异。
我们的结果表明，GLUT9 多态性与 MAFLD 显著相关，肝特异性敲除 Glut9 可显著降低肝内含量并改善小鼠饮食诱导的 MAFLD。
