Abstract
Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) that may lead to liver cirrhosis or hepatocellular carcinoma. Here, we examined the diagnostic utility of tri-antennary tri-sialylated mono-fucosylated glycan of alpha-1 antitrypsin (AAT-A3F), a non-invasive glycobiomarker identified in a previous study of NASH diagnosis. This study included 131 biopsy-proven Japanese patients with NAFLD. We evaluated the utility of AAT-A3F in NASH diagnosis, and conducted genetic analysis to analyse the mechanism of AAT-A3F elevation in NASH. Serum AAT-A3F concentrations were significantly higher in NASH patients than in NAFL patients, and in patients with fibrosis, lobular inflammation, and ballooning. Hepatic FUT6 gene expression was significantly higher in NASH than in NAFL. IL-6 expression levels were significantly higher in NASH than in NAFL and showed a positive correlation with FUT6 expression levels. The serum-AAT-A3F levels strongly correlated with hepatic FUT6 expression levels. AAT-A3F levels increased with fibrosis, pathological inflammation, and ballooning in patients with NAFLD and may be useful for non-invasive diagnosis of NASH from the early stages of fibrosis.
Highlights
Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) that may lead to liver cirrhosis or hepatocellular carcinoma
NAFLD is sub-divided into non-alcoholic fatty liver (NAFL; a non-progressive form of NAFLD) and non-alcoholic steatohepatitis (NASH; a progressive form that can lead to cirrhosis and the development of hepatocellular carcinoma [HCC]2–4)
In patients with NAFLD, NAFL shows a non-progressive clinical course, whereas NASH is a serious disease with a high risk of both overall and liver-related morbidity and mortality[2,3,4]
Summary
Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD) that may lead to liver cirrhosis or hepatocellular carcinoma. We examined the diagnostic utility of tri-antennary tri-sialylated mono-fucosylated glycan of alpha-1 antitrypsin (AAT-A3F), a non-invasive glycobiomarker identified in a previous study of NASH diagnosis. AAT-A3F levels increased with fibrosis, pathological inflammation, and ballooning in patients with NAFLD and may be useful for non-invasive diagnosis of NASH from the early stages of fibrosis. Mac-2-binding protein glycosylation isomer (M2BPGi) was reported as a novel fibrosis biomarker[13] and has shown utility in NAFLD14. As represented by these molecules, glycosylation changes reflecting liver disease severity are receiving increasing attention. We determined the N-glycomic profile of focused serum glycoproteins from patients with NAFL or NASH by focused protein glycomic analysis (FPG), and successfully discovered several NASH biomarker candidates. The simplified method enabled us to quantitatively measure AAT-A3F in a high-throughput manner
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