CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Mol Cell Endocrinol. 2023 Sep 15;575:112032. doi: 10.1016/j.mce.2023.112032. Epub 2023 Jul 25.
Progesterone and adipoQ receptor 9 (PAQR9) is an endoplasmic reticulum (ER)-localized membrane protein that is involved in protein quality control of ER by interacting with BAG6. One of the physiological functions of PAQR9 is regulation of fasting-induced ketogenesis and fatty acid oxidation in the liver via modulating protein degradation of PPARα. However, it is currently unknown whether or not PAQR9 impacts glucose homeostasis. We addressed this question using a Paqr9-deleted mouse model in which type 1 diabetes was induced by streptozotocin injection and type 2 diabetes was induced by high-fat diet (HFD) with streptozotocin injection. Paqr9 deletion improved hyperglycemia and glucose tolerance in both of the diabetic mouse models. In the pancreatic islets, Paqr9 deletion reduced apoptosis of β cells in type 2 diabetic mice. Paqr9 deletion also reduced HFD-induced hepatic steatosis and adiposity of white adipose tissue. In Min6 cells, overexpression of DUF3538 domain of BAG6 to block the interaction of PAQR9 with BAG6 was able to enhance glucose-stimulated insulin secretion upon treatment with inflammatory factors or thapsigargin, an ER stress inducer. Thapsigargin-induced ER stress markers were also reduced by overexpression of DUF3538 domain. Collectively, these results indicate that PAQR9 has a modulatory role in glucose homeostasis, associated with regulation on insulin secretion of β cells in vitro under stress conditions.
孕激素和脂肪组织 Q 受体 9（PAQR9）是一种内质网（ER）定位的膜蛋白，通过与 BAG6 相互作用参与 ER 的蛋白质质量控制。PAQR9 的生理功能之一是通过调节 PPARα 的蛋白降解来调节肝脏中的禁食诱导的酮体生成和脂肪酸氧化。然而，目前尚不清楚 PAQR9 是否影响血糖稳态。我们使用 Paqr9 缺失的小鼠模型解决了这个问题，该模型通过链脲佐菌素注射诱导 1 型糖尿病，通过高脂肪饮食（HFD）联合链脲佐菌素注射诱导 2 型糖尿病。Paqr9 缺失改善了两种糖尿病小鼠模型的高血糖和葡萄糖耐量。在胰岛中，Paqr9 缺失减少了 2 型糖尿病小鼠 β 细胞的凋亡。Paqr9 缺失还减少了 HFD 诱导的肝脂肪变性和白色脂肪组织的肥胖。在 Min6 细胞中，过表达 BAG6 的 DUF3538 结构域以阻断 PAQR9 与 BAG6 的相互作用，能够增强炎症因子或内质网应激诱导剂 thapsigargin 处理时的葡萄糖刺激的胰岛素分泌。过表达 DUF3538 结构域还降低了 thapsigargin 诱导的 ER 应激标志物。总之，这些结果表明，PAQR9 在血糖稳态中具有调节作用，与应激条件下体外 β 细胞胰岛素分泌的调节有关。
