Circulatory protein glycosylation is a biomarker of multiple disease and inflammatory states and has been applied in the clinic for liver dysfunction, heart disease and diabetes. With the notable exception of antibodies, the liver produces most of the circulatory glycoproteins, including the acute phase proteins released as a function of the inflammatory response. Among these proteins is β-galactoside α2,6-sialyltransferase (ST6Gal1), an enzyme required for α2,6-linked sialylation of glycoproteins. Here, we describe a hepatocyte-specific conditional knockout of ST6Gal1 (H-cKO) using albumin promoter-driven Cre-lox recombination. We confirm the loss of circulatory glycoprotein α2,6 sialylation and note no obvious dysfunction or pathology in young H-cKO mice, yet these mice show robust changes in plasma glycoprotein fucosylation, branching and the abundance of bisecting GlcNAc and marked changes in a number of metabolic pathways. As H-cKO mice aged, they spontaneously developed fatty liver disease characterized by the buildup of fat droplets in the liver, inflammatory cytokine production and a shift in liver leukocyte phenotype away from anti-inflammatory Kupffer cells and towards proinflammatory M1 macrophages. These findings connect hepatocyte and circulatory glycoprotein sialylation to the regulation of metabolism and inflammation, potentially identifying the glycome as a new target for liver-driven disease.

中文翻译：

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肝细胞唾液酸化的调节可导致自发性脂肪肝疾病和炎症。

循环蛋白糖基化是多种疾病和炎症状态的生物标记，已被用于肝功能不全，心脏病和糖尿病的临床中。除抗体外，肝脏产生大多数循环糖蛋白，包括根据炎症反应释放的急性期蛋白。这些蛋白质中有β-半乳糖苷α2,6-唾液酸转移酶（ST6Gal1），这是糖蛋白与α2,6-连接的唾液酸化所必需的酶。在这里，我们描述了使用白蛋白启动子驱动的Cre-lox重组对ST6Gal1（H-cKO）的肝细胞特异性条件性剔除。我们确认了循环糖蛋白α2,6唾液酸化的丧失，并注意到在年轻的H-cKO小鼠中没有明显的功能障碍或病理，但这些小鼠的血浆糖蛋白岩藻糖基化表现出强劲的变化，分支和二等分的GlcNAc的丰度以及许多代谢途径的明显变化。随着H-cKO小鼠的衰老，他们自发地发展为脂肪肝疾病，其特征是肝脏中脂肪滴的堆积，炎性细胞因子的产生以及肝白细胞表型从抗炎性库普弗细胞向促炎性M1巨噬细胞转移。这些发现将肝细胞和循环糖蛋白唾液酸化与代谢和炎症的调节联系起来，有可能将糖原鉴定为肝病疾病的新靶标。炎症细胞因子的产生和肝白细胞表型从抗炎性库普弗细胞向促炎性M1巨噬细胞的转移。这些发现将肝细胞和循环糖蛋白唾液酸化与代谢和炎症的调节联系起来，有可能将糖原鉴定为肝病疾病的新靶标。炎症细胞因子的产生和肝白细胞表型从抗炎性库普弗细胞向促炎性M1巨噬细胞的转移。这些发现将肝细胞和循环糖蛋白唾液酸化与代谢和炎症的调节联系起来，潜在地将糖原鉴定为肝病疾病的新靶标。