Circulating Foamy CD36hi Ly6Clo Monocytes in Mouse Models of Diabetic Dyslipidemia

Diabetes increases the risk for cardiovascular disease (CVD) and diabetic kidney disease (DKD). Increased levels of triglyceride-rich lipoproteins (TRLs), a hallmark of diabetic dyslipidemia, associate with CVD and DKD. Monocytes become lipid-laden in response to hypercholesterolemia, but it is unclear if and how diabetic dyslipidemia induces monocyte lipid accumulation. To test if diabetes promotes foamy monocytes in circulation, we examined monocyte lipid-loading in three mouse models of diabetes with varying degrees of dyslipidemia and increases in TRLs: two mouse models of type 1 diabetes [streptozotocin (STZ)-induced diabetes (STZ-D) and viral mimicry-induced diabetes (LCMV-D)], and a model of type 2 diabetes (BTBR Lep ob;OB), all with human-like dyslipidemia generated by LDL receptor deletion. Diabetes resulted in elevated lipid loading of Ly6Clo blood monocytes in all models of diabetes, as determined by flow cytometry staining for perilipin-2 (PLN2), a marker of mature intracellular lipid droplets or BODIPY. PLN2 mean fluorescence intensity (MFI) in STZ-D was increased 1.4 ± 0.2-fold compared with nondiabetic (ND) mice, n=8-13, p=0.029, and 1.6 ± 0.1-fold in LCMV-D compared with ND mice, n=11-13, p<0.0001, while BODIPY was increased 2.2 ± 0.1-fold in BTBR OB vs. ND BTBR controls, n=6-11, p<0.0001. Moreover, Ly6Clo monocytes exhibited higher MFI of the scavenger receptor CD36 in the presence of diabetes (1.6 ± 0.2-fold in LCMV-D vs. ND, n=6, p=0.015). To further explore if diabetes increases monocyte lipid-loading via CD36, monocytes from ND and D mice were cultured with VLDL in the presence or absence of an CD36 inhibitor (sulfo-N-succinimidyl oleate). Diabetes augmented ex vivo lipid loading by VLDL, and VLDL monocyte lipid-loading was prevented by blocking CD36. These findings suggest that diabetes increases Ly6Clo monocyte CD36 levels, allowing increased lipid uptake in circulation, which may contribute to atherosclerosis and DKD. Disclosure J. Cervantes: None. F. Kramer: None. K. Bornfeldt: Advisory Panel; ESPERION Therapeutics, Inc. Other Relationship; American Heart Association. J.E. Kanter: None. Funding National Institutes of Health (R01DK121756)