CD36 maintains lipid homeostasis via selective uptake of monounsaturated fatty acids during matrix detachment and tumor progression.

Cell metabolism Pub Date : 2023-11-07 Epub Date: 2023-10-17 DOI:10.1016/j.cmet.2023.09.012
Alexander R Terry, Veronique Nogueira, Hyunsoo Rho, Gopalakrishnan Ramakrishnan, Jing Li, Soeun Kang, Koralege C Pathmasiri, Sameer Ahmed Bhat, Liping Jiang, Shafi Kuchay, Stephanie M Cologna, Nissim Hay
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Abstract

A high-fat diet (HFD) promotes metastasis through increased uptake of saturated fatty acids (SFAs). The fatty acid transporter CD36 has been implicated in this process, but a detailed understanding of CD36 function is lacking. During matrix detachment, endoplasmic reticulum (ER) stress reduces SCD1 protein, resulting in increased lipid saturation. Subsequently, CD36 is induced in a p38- and AMPK-dependent manner to promote preferential uptake of monounsaturated fatty acids (MUFAs), thereby maintaining a balance between SFAs and MUFAs. In attached cells, CD36 palmitoylation is required for MUFA uptake and protection from palmitate-induced lipotoxicity. In breast cancer mouse models, CD36-deficiency induced ER stress while diminishing the pro-metastatic effect of HFD, and only a palmitoylation-proficient CD36 rescued this effect. Finally, AMPK-deficient tumors have reduced CD36 expression and are metastatically impaired, but ectopic CD36 expression restores their metastatic potential. Our results suggest that, rather than facilitating HFD-driven tumorigenesis, CD36 plays a supportive role by preventing SFA-induced lipotoxicity.

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CD36在基质分离和肿瘤进展过程中通过选择性摄取单不饱和脂肪酸来维持脂质稳态。
高脂肪饮食(HFD)通过增加饱和脂肪酸(SFAs)的摄取来促进转移。脂肪酸转运蛋白CD36参与了这一过程,但缺乏对CD36功能的详细了解。在基质脱离过程中,内质网(ER)应激降低SCD1蛋白,导致脂质饱和度增加。随后,CD36以p38和AMPK依赖的方式被诱导,以促进单不饱和脂肪酸(MUFA)的优先摄取,从而维持SFAs和MUFA之间的平衡。在附着的细胞中,CD36棕榈酰化是MUFA摄取和保护免受棕榈酸诱导的脂毒性所必需的。在癌症小鼠模型中,CD36缺乏诱导了ER应激,同时减少了HFD的促增殖作用,只有棕榈酰化有效的CD36挽救了这种作用。最后,AMPK缺陷型肿瘤的CD36表达减少,并且转移受损,但异位CD36表达恢复了其转移潜力。我们的研究结果表明,CD36不是促进HFD驱动的肿瘤发生,而是通过预防SFA诱导的脂毒性发挥支持作用。
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