Fish Shellfish Immunol 2023 Aug 01;139:108863. doi: 10.1016/j.fsi.2023.108863.

ATGL-mediated lipophagy balances cholesterol-induced inflammation in pathogen infected Apostichopus japonicus coelomocytes.

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Cholesterol metabolism can be dynamically altered in response to pathogen infection that ensure proper macrophage inflammatory function in mammals. However, it is unclear whether the dynamic between cholesterol accumulation and breakdown could induce or suppress inflammation in aquatic animal. Here, we aimed to investigate the cholesterol metabolic response to LPS stimulation in coelomocytes of Apostichopus japonicus, and to elucidate the mechanism of lipophagy in regulating cholesterol-related inflammation. LPS stimulation significantly increased intracellular cholesterol levels at early time point (12 h), and the increase in cholesterol levels is associated with AjIL-17 upregulation. Excessive cholesterol in coelomocytes of A. japonicus was rapidly converted to cholesteryl esters (CEs) and stored in lipid droplets (LDs) after 12 h of LPS stimulation and prolonged for 18 h. Then, increased colocalization of LDs with lysosomes was observed at late time point of LPS treatment (24 h), accompanied by elevated expression of AjLC3 and decreased expression of Ajp62. At the same time, the expression of AjABCA1 rapidly increased, suggesting lipophagy induction. Moreover, we demonstrated that AjATGL is required for induction of lipophagy. Inducing lipophagy by AjATGL overexpression attenuated cholesterol-induced AjIL-17 expression. Overall, our study provides evidence that cholesterol metabolic response occurs upon LPS stimulation, which is actively involved in regulating the inflammatory response of coelomocytes. AjATGL-mediated lipophagy is responsible for cholesterol hydrolysis, thereby balancing cholesterol-induced inflammation in the coelomocytes of A. japonicus.

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