Chromatin accessibility analysis in lipid droplet-laden macrophages with or without SLC27A1 silencing (ATAC-seq)
The obesity epidemic is associated with increased incidence of colorectal cancer liver metastasis (CRLM) and the local recurrence following CRLM resection. Here, we demonstrate that M2 type tumor-associated macrophages (TAMs) significantly accumulate within liver metastases in high-fat-diet-induced obese mice, and thus accelerating the development of CRLM. The TAMs from mice with high-fat diet facilitate the expansion of lipid droplets by upregulating SLC27A1, and as a result, M2 polarization is promoted. Mechanistically, SLC27A1 binds with PLIN2, a lipid droplet coat protein, to inhibit its degradation via chaperone-mediated autophagy. Moreover, the number of SLC27A1+ TAMs is significantly increased in obese patients with CRLM, suggesting that the mechanism revealed here likely plays a role in the progression of human CRLM and represents a potential target for treatment. Overall design: The bone marrow-derived macrophages (BMDMs) were obtained from 6-week-old C57BL/6 mice through culturing in 20% L929-derived conditioned medium for 7 days. The BMDMs were transfected with siNC and siSLC27A1 following incubation with MC38-derived conditioned medium (CM) and 200 nM a-linolenic acid for 24 hours to induce lipid-associated macrophages (LAMs).