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Chromatin accessibility analysis in lipid droplet-laden macrophages with or without SLC27A1 silencing (ATAC-seq)

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE313205 | GEO | 2026/01/31

REPOSITORIES: GEO

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Project description:Aims/hypothesis: While lipid deposition in skeletal muscle is considered to be involved in obesity-associated insulin resistance, neutral intramyocellular lipid (IMCL) accumulation per se does not necessarily induce insulin resistance. We previously demonstrated that overexpression of the lipid droplet coat protein perilipin 2 augments intramyocellular lipid content while improving insulin sensitivity. Another member of the perilipin family, perilipin 5 (PLIN5), is predominantly expressed in oxidative tissues like skeletal muscle. Here we investigated the effects of PLIN5 overexpression M-bM-^@M-^S in comparison with effects of PLIN2 M-bM-^@M-^S on skeletal muscle lipid levels, gene expression profiles and insulin sensitivity. Methods: Gene electroporation was used to overexpress PLIN5 in tibialis anterior muscle of rats fed a high fat diet. Eight days after electroporation, insulin-mediated glucose uptake in skeletal muscle was measured by means of a hyperinsulinemic euglycemic clamp. Electron microscopy, fluorescence microscopy and lipid extractions were performed to investigate IMCL accumulation. Gene expression profiles were obtained using microarrays. Results: TAG storage and lipid droplet size increased upon PLIN5 overexpression. Despite the higher IMCL content, insulin sensitivity was not impaired and DAG and acylcarnitine levels were unaffected. In contrast to the effects of PLIN2 overexpression, microarray data analysis revealed a gene expression profile favoring FA oxidation and improved mitochondrial function. Conclusions/interpretation: Both PLIN2 and PLIN5 increase neutral IMCL content without impeding insulin-mediated glucose uptake. As opposed to the effects of PLIN2 overexpression, overexpression of PLIN5 in skeletal muscle promoted expression of a cluster of genes under control of PPARM-NM-1 and PGC1M-NM-1 involved in FA catabolism and mitochondrial oxidation. Rats received a high fat diet for 3 weeks; 2 weeks after start of the diet intervention Plin5 (OXPAT) or Plin2 (ADRP) were overexpressed in either the right or left tibialis anterior muscle. One week later pooled tibialis anterior muscle samples were analysed on microarrays.

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Chromatin accessibility analysis in lipid droplet-laden macrophages with or without SLC27A1 silencing (ATAC-seq)

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