p32 regulates ER stress and lipid homeostasis by down-regulating GCS1 expression
p32 regulates ER stress and lipid homeostasis by down-regulating GCS1 expression
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p32 通过下调 GCS1 表达来调节 ER 应激和脂质稳态
DOI：
10.1096/fj.201701004rr
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发表时间：
2018-07-01
期刊：
影响因子：
4.8
通讯作者：
Zhang, Yanping
中科院分区：
文献类型：
--
作者：
Liu, Yong;Leslie, Patrick L.;Zhang, Yanping
持续的内质网（ER）应激在许多代谢疾病的发展中起着重要作用，包括心血管疾病、非酒精性脂肪肝、胰岛素抵抗、肥胖和糖尿病。 p32 是一种多室蛋白，参与氧化磷酸化和葡萄糖氧化的调节。 p32 消融与对年龄相关和饮食引起的肥胖的抵抗力有关，其机制目前尚不清楚。在这里，我们发现 p32 通过调节脂肪酸诱导的内质网应激来促进脂质生物合成。我们发现 p32 与内质网锚定酶甘露糖基低聚糖葡萄糖苷酶 I (GCS1) 相互作用，GCS1 是一种内质网锚定的葡萄糖苷酶，对于 N 连接糖蛋白的加工至关重要，并以溶酶体依赖性方式还原 GCS1。我们证明，GCS1 表达增加可以减轻脂肪酸诱导的 ER 应激，并且对于抑制 ER 应激相关的脂肪生成基因激活至关重要，如 Srebp1、Fasn 和 Acc 的下调所证明的那样。一致地，抑制 p32 会导致 GCS1 表达增加，并减轻脂肪酸诱导的 ER 应激，从而减少脂质积累。因此，p32 和 GCS1 是 ER 功能和脂质稳态的调节因子，是治疗肥胖和糖尿病的潜在治疗靶点。Liu, Y.、Leslie, P. L.、Jin, A.、Itahana, K.、Graves, L. M.、Zhang, Y. p32 通过下调 GCS1 表达来调节 ER 应激和脂质稳态。
Sustained endoplasmic reticulum (ER) stress plays a major role in the development of many metabolic diseases, including cardiovascular disease, nonalcoholic fatty liver disease, insulin resistance, obesity, and diabetes. p32 is a multicompartmental protein involved in the regulation of oxidative phosphorylation and glucose oxidation. p32 ablation is associated with resistance to age-associated and diet-induced obesity through a mechanism that remains largely unknown. Here, we show that p32 promotes lipid biosynthesis by modulating fatty acid-induced ER stress. We found that p32 interacts with endoplasmic reticulum-anchored enzyme mannosyl-oligosaccharide glucosidase I (GCS1), an ER lumen-anchored glucosidase that is essential for the processing of N-linked glycoproteins, and reduces GCS1 in a lysosome-dependent manner. We demonstrate that increased GCS1 expression alleviates fatty acid-induced ER stress and is critical for suppressing ER stress-associated lipogenic gene activation, as demonstrated by the down-regulation of Srebp1, Fasn, and Acc. Consistently, suppression of p32 leads to increased GCS1 expression and alleviates fatty acid-induced ER stress, resulting in reduced lipid accumulation. Thus, p32 and GCS1 are regulators of ER function and lipid homeostasis and are potential therapeutic targets for the treatment of obesity and diabetes.Liu, Y., Leslie, P. L., Jin, A., Itahana, K., Graves, L. M., Zhang, Y. p32 regulates ER stress and lipid homeostasis by down-regulating GCS1 expression.