Journal
EBIOMEDICINE
Volume 56, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ebiom.2020.102797
Keywords
CD36; Preadipocytes; Inflammation; Lysosomal calcium; IP3R1
Funding
- National Key R&D Program of China [2018YFC1312700]
- National Natural Science Foundation of China [81873569, 81970510, 31971084]
- Science and Technology Research Program of Chongqing Municipal Education Commission [KJZD-K201800401, KJQN201900438]
- Talent Project of Chongqing [CQYC2019050790]
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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.
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