Hepatic F-Box Protein FBXW7 Maintains Glucose Homeostasis Through Degradation of Fetuin-A
Hepatic F-Box Protein FBXW7 Maintains Glucose Homeostasis Through Degradation of Fetuin-A
复制标题
肝脏 F-Box 蛋白 FBXW7 通过降解胎球蛋白-A 维持血糖稳态
DOI：
10.2337/db17-1348
复制
发表时间：
2018-05-01
期刊：
影响因子：
7.7
通讯作者：
Li, Xiaoying
中科院分区：
文献类型：
--
作者：
Zhao, Jiejie;Xiong, Xuelian;Li, Xiaoying
2型糖尿病（T2DM）已成为对人类健康最严重、最长期的威胁之一。然而，将肥胖与胰岛素抵抗联系起来的分子机制仍然很大程度上未知。在这里，我们发现含有 F-box 和 WD 重复结构域的 7 (FBXW7)（一种 E3 泛素蛋白连接酶）在两种肥胖小鼠模型和肥胖人类受试者的肝脏中显着下调。我们进一步在中国人群中发现了一种功能性低频人类 FBXW7 编码变异 (p.Ala204Thr)，该变异与血糖升高和 T2DM 风险相关。值得注意的是，肝脏特异性敲除 FBXW7 的小鼠即使在正常饮食下也会出现高血糖、葡萄糖不耐受和胰岛素抵抗。相反，肝脏中 FBXW7 的过度表达不仅可以防止高脂肪饮食诱导的胰岛素抵抗的发展，还可以减轻肥胖小鼠的疾病特征。从机制上讲，FBXW7 直接与肝因子胎球蛋白-A 结合，诱导其泛素化和随后的蛋白酶体降解，这是维持葡萄糖稳态的重要机制。因此，我们提供的证据显示 FBXW7 在葡萄糖稳态中的有益作用。
Type 2 diabetes mellitus (T2DM) has become one of the most serious and long-term threats to human health. However, the molecular mechanism that links obesity to insulin resistance remains largely unknown. Here, we show that F-box and WD repeat domain-containing 7 (FBXW7), an E3 ubiquitin protein ligase, is markedly downregulated in the liver of two obese mouse models and obese human subjects. We further identify a functional low-frequency human FBXW7 coding variant (p.Ala204Thr) in the Chinese population, which is associated with elevated blood glucose and T2DM risk. Notably, mice with liver-specific knockout of FBXW7 develop hyperglycemia, glucose intolerance, and insulin resistance even on a normal chow diet. Conversely, overexpression of FBXW7 in the liver not only prevents the development of high-fat diet–induced insulin resistance but also attenuates the disease signature of obese mice. Mechanistically, FBXW7 directly binds to hepatokine fetuin-A to induce its ubiquitination and subsequent proteasomal degradation, comprising an important mechanism maintaining glucose homeostasis. Thus, we provide evidence showing a beneficial role of FBXW7 in glucose homeostasis.