Hang Zeng1, Chenxi Tang2, Bingru Lin2, Mengli Yu2, Xinyu Wang2, Jinghua Wang2, Shenghui Chen3, Chaohui Yu2. 1. Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China. zenghang@zju.edu.cn. 2. Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China. 3. Department of Gastroenterology, School of Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University, Hangzhou, 310003, China.
Abstract
BACKGROUND: 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. METHODS: 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 (Glut9Hep-ko) were generated to investigate the role of hepatic GLUT9 in MAFLD in male mice. RESULTS: We found that the GA/AA genotypes (rs1014290) were associated with elevated serum UA levels in MAFLD patients. Meanwhile, we found that Glut9Hep-ko 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 Glut9Fl/Fl littermates. However, Glut9Hep-ko mice and wild-type littermates showed no significant difference on hepatic fatty acid oxidation or inflammation. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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 (Glut9Hep-ko) were generated to investigate the role of hepatic GLUT9 in MAFLD in male mice. RESULTS: We found that the GA/AA genotypes (rs1014290) were associated with elevated serum UA levels in MAFLD patients. Meanwhile, we found that Glut9Hep-ko 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 Glut9Fl/Fl littermates. However, Glut9Hep-ko mice and wild-type littermates showed no significant difference on hepatic fatty acid oxidation or inflammation. CONCLUSIONS: 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.