Obesity induces preadipocyte CD36 expression promoting inflammation via the disruption of lysosomal calcium homeostasis and lysosome function
Obesity induces preadipocyte CD36 expression promoting inflammation via the disruption of lysosomal calcium homeostasis and lysosome function
复制标题
肥胖诱导前脂肪细胞 CD36 表达，通过破坏溶酶体钙稳态和溶酶体功能促进炎症
DOI：
10.1016/j.ebiom.2020.102797
复制
发表时间：
2020-06-01
期刊：
影响因子：
11.1
通讯作者：
Chen, Yaxi
中科院分区：
文献类型：
--
作者：
Luo, Xiaoxiao;Li, Yanping;Chen, Yaxi
背景：前脂肪细胞与肥胖引起的炎症密切相关。在肥胖小鼠的脂肪组织中观察到溶酶体功能缺陷导致自噬通量受损。虽然脂肪酸转位酶 CD36 是一种重要的免疫代谢受体，但目前尚不清楚前脂肪细胞 CD36 是否参与脂肪组织炎症以及 CD36 是否调节溶酶体功能。方法：使用肥胖患者的内脏脂肪组织、高脂饮食 (HFD) 诱导的肥胖小鼠模型、原代小鼠前脂肪细胞和 3T3L1 细胞，我们分析了前脂肪细胞 CD36 是否以及如何调节溶酶体功能和脂肪组织炎症。研究结果：肥胖患者和高脂饮食小鼠的前脂肪细胞中 CD36 表达被诱导，并伴有溶酶体功能的破坏。 CD36 敲除可保护 HFD 喂养小鼠的原代前脂肪细胞免受溶酶体损伤。在体外，CD36 与 Fyn 相互作用，磷酸化并激活肌醇 (1,4,5)-三磷酸受体 1 (IP3R1)，导致过量的钙从内质网 (ER) 转运至溶酶体，从而导致溶酶体损伤和炎症。此外，IP3R抑制剂2-氨基乙氧基二苯硼酸盐(2APB)可减轻CD36过度表达的前脂肪细胞中的溶酶体损伤、炎症和脂质积累。解释：我们的数据支持前脂肪细胞中CD36的异常上调可能有助于脂肪组织炎症的发生。 CD36/Fyn/IP3R1 介导的溶酶体钙超载导致前脂肪细胞溶酶体损伤和炎症。因此，以改善溶酶体钙稳态为目标可能代表了治疗肥胖引起的炎症的一种新策略。 (C) 2020 作者。由 Elsevier B.V. 出版
Background: Preadipocyte is closely related to obesity-induced inflammation. The impairment of autophagic flux by defective lysosomal function has been observed in adipose tissue from obese mice. While the fatty acid translocase CD36 is an important immuno-metabolic receptor, it remains unclear whether preadipocyte CD36 is involved in adipose tissue inflammation and whether CD36 regulates lysosomal function.Methods: Using visceral adipose tissue from obese patients, a high-fat diet (HFD)-induced obese mice model, primary mouse preadipocytes and 3T3L1 cells we analyzed whether and how preadipocyte CD36 modulates lysosomal function and adipose tissue inflammation.Findings: CD36 expression in preadipocytes is induced in obese patients and HFD-fed mice, accompanied with the disruption of lysosome function. CD36 knockout protects primary preadipocytes of HFD-fed mice from lysosomal impairment. In vitro, CD36 interacts with Fyn to phosphorylate and activate Inositol (1,4,5)-trisphosphate receptor 1 (IP3R1), causing excess calcium transport from endoplasmic reticulum (ER) to lysosome, which results in lysosomal impairment and inflammation. Moreover, IP3R inhibitor 2-aminoethoxydiphenyl borate (2APB) attenuates lysosomal impairment, inflammation and lipid accumulation in CD36-overexpressing preadipocytes.Interpretation: Our data support that the abnormal upregulation of CD36 in preadipocytes may contribute to the development of adipose tissue inflammation. CD36/Fyn/IP3R1-mediated lysosomal calcium overload leads to lysosomal impairment and inflammation in preadipocyte. Thus targeting improving lysosomal calcium homeostasis may represent a novel strategy for treating obesity-induced inflammation. (C) 2020 The Author(s). Published by Elsevier B.V.