Hepatic sialic acid synthesis modulates glucose homeostasis in both liver and skeletal muscle.
Hepatic sialic acid synthesis modulates glucose homeostasis in both liver and skeletal muscle.
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DOI：
10.1016/j.molmet.2023.101812
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发表时间：
2023-12
影响因子：
8.1
通讯作者：
Mineo, Chieko
中科院分区：
文献类型：
--
作者：
Peng, Jun;Yu, Liming;Huang, Linzhang;Paschoal, Vivian A.;Chu, Haiyan;de Souza, Camila O.;Varre, Joseph V.;Oh, Da Young;Kohler, Jennifer J.;Xiao, Xue;Xu, Lin;Holland, William L.;Shaul, Philip W.;Mineo, Chieko
唾液酸是糖蛋白和糖脂中聚糖的末端单糖，其从葡萄糖的衍生受限速酶UDP-GlcNAc 2-差向异构酶/ManNAc激酶（GNE）调节。尽管控制葡萄糖代谢的关键内源性肝脏蛋白上的聚糖被唾液酸化，但肝脏中唾液酸合成和唾液酸化如何影响葡萄糖稳态尚不清楚。研究旨在填补这一知识空白。为了减少肝细胞中唾液酸和唾液酸化的产生，产生了肝细胞特异性GNE敲低小鼠模型，并在体内或原代肝细胞中评价了全身葡萄糖代谢、肝胰岛素信号传导和胰高血糖素信号传导。还评估了外周胰岛素敏感性。此外，确定了肝脏中唾液酸化影响肝脏胰岛素信号传导和胰高血糖素信号传导以及外周胰岛素敏感性的机制。小鼠肝脏GNE缺失导致胰岛素抑制肝脏葡萄糖产生受损。这是由于肝脏胰岛素受体（IR）的唾液酸化减少和通过Eph受体B4过度降解导致的IR丰度下降。肝GNE缺乏还导致肝胰高血糖素受体（GCGR）功能钝化，这与其唾液酸化和胰高血糖素亲和力下降有关。伴随的肝FGF 21产生的上调引起骨骼肌葡萄糖处置的增强，这导致葡萄糖耐量和胰岛素敏感性的总体增加。这些集体观察揭示了肝脏唾液酸合成和唾液酸化调节肝脏和骨骼肌中的葡萄糖稳态。通过询问肝脏唾液酸合成如何影响肝脏中的葡萄糖控制机制，已经确定了一个新的代谢循环，其中由葡萄糖产生的聚糖的关键成分调节其前体的全身控制。肝脏中唾液酸合成的损失导致肝脏胰岛素抵抗。肝脏胰岛素抵抗是由于胰岛素受体降解增加所致。肝脏中唾液酸合成的缺失会减弱胰高血糖素受体的功能。胰高血糖素受体功能障碍是由于对胰高血糖素的亲和力下降。肝脏中唾液酸合成的损失增加了肌肉通过FGF 21的葡萄糖处置。
Sialic acid is a terminal monosaccharide of glycans in glycoproteins and glycolipids, and its derivation from glucose is regulated by the rate-limiting enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE). Although the glycans on key endogenous hepatic proteins governing glucose metabolism are sialylated, how sialic acid synthesis and sialylation in the liver influence glucose homeostasis is unknown. Studies were designed to fill this knowledge gap. To decrease the production of sialic acid and sialylation in hepatocytes, a hepatocyte-specific GNE knockdown mouse model was generated, and systemic glucose metabolism, hepatic insulin signaling and glucagon signaling were evaluated in vivo or in primary hepatocytes. Peripheral insulin sensitivity was also assessed. Furthermore, the mechanisms by which sialylation in the liver influences hepatic insulin signaling and glucagon signaling and peripheral insulin sensitivity were identified. Liver GNE deletion in mice caused an impairment of insulin suppression of hepatic glucose production. This was due to a decrease in the sialylation of hepatic insulin receptors (IR) and a decline in IR abundance due to exaggerated degradation through the Eph receptor B4. Hepatic GNE deficiency also caused a blunting of hepatic glucagon receptor (GCGR) function which was related to a decline in its sialylation and affinity for glucagon. An accompanying upregulation of hepatic FGF21 production caused an enhancement of skeletal muscle glucose disposal that led to an overall increase in glucose tolerance and insulin sensitivity. These collective observations reveal that hepatic sialic acid synthesis and sialylation modulate glucose homeostasis in both the liver and skeletal muscle. By interrogating how hepatic sialic acid synthesis influences glucose control mechanisms in the liver, a new metabolic cycle has been identified in which a key constituent of glycans generated from glucose modulates the systemic control of its precursor. Loss of sialic acid synthesis in the liver causes hepatic insulin resistance. The hepatic insulin resistance is due to increased insulin receptor degradation. Loss of sialic acid synthesis in the liver blunts glucagon receptor function. The glucagon receptor dysfunction is due to deceased affinity for glucagon. Loss of sialic acid synthesis in liver increases muscle glucose disposal via FGF21.
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DOI：
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发表时间：
2018-12-01
影响因子：
3
作者：
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DOI：
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影响因子：
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