Department of Advanced Metabolic Hepatology, Osaka University Graduate School of Medicine, 1-7, Yamada-Oka, Suita, Osaka, 565-0871, Japan.
Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, 1-7, Yamada-Oka, Suita, Osaka, 565-0871, Japan.
Glycoconj J. 2024 Oct;41(4-5):267-278. doi: 10.1007/s10719-024-10163-w. Epub 2024 Sep 9.
Recent findings in glycobiology revealed direct evidence of the involvement of oligosaccharide changes in human diseases, including liver diseases. Fucosylation describes the attachment of a fucose residue to a glycan or glycolipid. We demonstrated that fucosylated proteins are useful serum biomarkers for nonalcoholic fatty liver disease. Among fucosyltransferases, expression of alpha-1, 6-fucosyltransferase (Fut8), which produces core fucose, is frequently elevated during the progression of human chronic liver diseases. Previously, we discovered core-fucose-specific Pholiota squarrosa lectin (PhoSL) from Japanese mushroom Sugitake. Lectins are bioactive compounds that bind to glycan specifically, and various kinds of lectin have a variety of biological functions. Using high-fat and high-cholesterol (HFHC)-fed steatohepatitic mice, we found that core fucosylation increases in hepatic inflammatory macrophages. Antibody drugs bind to specific antigens and block protein function. We hypothesized that, like antibody drugs, PhoSL could have inhibitory effects on glycoproteins involved in steatohepatitis progression. PhoSL administration dramatically decreased hepatic macrophage infiltration and liver fibrosis-related gene expression. Using mouse macrophage-like cell RAW264.7, we found that PhoSL enhanced core-fucose-mediated activation of macrophage cell death by blocking interferon-γ/signal transducer and activator of transcription 1 (STAT1) signaling. Core-fucose-mediated cell death is a mechanism for the anti-inflammatory effects and anti-fibrotic effects of PhoSL on activated macrophages in steatohepatitic liver. In addition, PhoSL provides an anti-fibrotic effect by blocking transforming growth factor-β/SMAD family member 3 signaling in hepatic stellate cells. In conclusion, we found core-fucose-specific PhoSL administration could suppress steatohepatitis progression by decreasing inflammatory macrophage infiltration and fibrotic signaling in hepatic stellate cells.
糖生物学的最新研究结果表明，寡糖变化直接参与人类疾病，包括肝脏疾病。岩藻糖化描述了岩藻糖残基与聚糖或糖脂的连接。我们证明了岩藻糖化蛋白是用于非酒精性脂肪性肝病的有用血清生物标志物。在岩藻糖基转移酶中，产生核心岩藻糖的α-1,6-岩藻糖基转移酶（Fut8）的表达在人类慢性肝病的进展过程中经常升高。之前，我们从日本蘑菇松茸中发现了核心岩藻糖特异性的鳞伞素（PhoSL）。凝集素是特异性结合聚糖的生物活性化合物，各种凝集素具有多种生物学功能。使用高脂肪和高胆固醇（HFHC）喂养的 steatohepatitic 小鼠，我们发现肝炎症性巨噬细胞中的核心岩藻糖化增加。抗体药物与特定抗原结合并阻断蛋白质功能。我们假设，像抗体药物一样，PhoSL 可能对参与 steatohepatitis 进展的糖蛋白具有抑制作用。PhoSL 给药可显著减少肝巨噬细胞浸润和与肝纤维化相关的基因表达。使用小鼠巨噬细胞样细胞 RAW264.7，我们发现 PhoSL 通过阻断干扰素-γ/信号转导和转录激活因子 1（STAT1）信号来增强核心岩藻糖介导的巨噬细胞细胞死亡。核心岩藻糖介导的细胞死亡是 PhoSL 在 steatohepatitic 肝脏中对活化巨噬细胞发挥抗炎和抗纤维化作用的机制。此外，PhoSL 通过阻断转化生长因子-β/SMAD 家族成员 3 在肝星状细胞中的信号转导发挥抗纤维化作用。总之，我们发现核心岩藻糖特异性 PhoSL 给药可通过减少炎症性巨噬细胞浸润和肝星状细胞中的纤维化信号来抑制 steatohepatitis 的进展。
