Chronic kidney disease induces distinct alterations of macrophage lipid metabolism in a mouse model of atherosclerosis

Chronic kidney disease (CKD) is associated with altered lipid metabolism and chronic inflammation, which both contribute to an accelerated risk of atherosclerotic cardiovascular disease. Macrophage polarization towards a pro-inflammatory phenotype plays a key role in atherosclerotic cardiovascular disease development and is mediated by a rewiring of macrophage immunometabolism. While prior studies have investigated associations between the systemic lipidome and CKD-accelerated CVD, the impact of CKD on macrophage lipid metabolism remains unknown. In this study, we profiled the macrophage lipidome in mice with and without CKD induced by 5/6 nephrectomy. After 16 weeks of a high-fat diet, thioglycollate-elicited peritoneal macrophages (PMΦ) were collected and subjected to lipidomics by LC-MS/MS. Quantification of 481 distinct lipids across 19 lipid classes identified an increased abundance of saturated C16-C24 FFAs, phosphatidylglycerols, phosphatidylethanolamines, modified ceramides, and polyunsaturated ether lipids in PMΦ from CKD mice compared to controls. PMΦ from CKD mice also exhibited decreased abundance of unsaturated FFAs, triglycerides and phosphatidylcholines. Long-chain-to-intermediate-chain acylcarnitine ratio, a metric of β-oxidation efficiency, was reduced in CKD PMΦ, without altering macrophage de novo lipogenesis suggesting a shunting of exogenous lipids towards complex lipid synthesis. Pathway enrichment analysis identified long-chain acyl-CoA synthetase 1 (ACSL1) as a potential upstream mediator of these observed changes in macrophage lipid metabolism. Expression of Acsl1 and inflammatory cytokines was increased in CKD PMΦ or following treatment with palmitate or uremic serum in RAW 264.7 macrophages. These effects were blunted by the knockdown of ACSL1 in RAW264.7 cells. Partitioning of fatty acids towards complex lipid synthesis by ACSL1 may be a mechanism underlying chronic inflammation in advancing CKD.