CKD Induces Distinct Alterations in Macrophage Lipid Metabolism in a Mouse Model of Atherosclerosis

Background: Chronic kidney disease (CKD) is associated with dyslipidemia and chronic inflammation which both contribute to macrophage foam cell formation and accelerated cardiovascular disease (CVD). While prior studies have investigated associations between the plasma lipidome and CVD, the impact of CKD on macrophage lipid metabolism remains unknown. Methods: We profiled the macrophage lipidome in low-density lipoprotein receptor deficient mice with and without CKD induced by 5/6 nephrectomy. Thioglycolate-elicited peritoneal macrophages (PMΦ) were collected after 16 weeks of high-fat diet, and targeted lipidomics was performed by LC-MS/MS to quantify 824 distinct lipids across 16 lipid classes. Changes in lipid classes between groups was compared using mixed linear models. Pathway enrichment analysis was used to identify potential causal lipid metabolic pathways. Results: Lipidomic analysis identified an increased abundance of saturated fatty acids, phosphatidylglycerols, phosphatidylethanolamines, and lactosyl-ceramides in PMΦ from CKD mice compared to controls. Long–to–intermediate-chain acylcarnitine ratio was reduced in CKD PMΦ, suggesting a shunting of fatty acids from β-oxidation towards complex lipid synthesis. Pathway enrichment analysis identified long-chain acyl CoA synthetases (ACSLs) as a potential upstream mediator. Expression of ACSL1, the primary macrophage ACSL, and multiple inflammatory cytokines was increased in CKD PMΦ compared to controls. Conclusion: CKD induces distinct alterations in macrophage lipid metabolism. Impaired β-oxidation and partitioning of fatty acids towards complex lipid synthesis by ACSL1 may be a mechanism underlying chronic inflammation in advancing CKD. Funding: Private Foundation SupportLipid classes with increased (A) and decreased (B) standardized mean abundance in CKD PMΦ compared to controls. Red and blue bars represent the respective increase and decrease in the corresponding lipid class. P values for the effect of CKD status on lipid class level from linear mixed models and adjusted for multiple comparisons.