CD36 serves as a signaling receptor and Free Fatty Acid (FFA) transporter in dyslipidemia: the role of dapagliflozin and alirocumab in downregulating atherogenic dyslipidemia via FFA uptake inhibition– experimental study

Background: Atherogenic dyslipidemia remains an essential predictor of cardiovascular disease. This study tested whether combined dapagliflozin and alirocumab therapy could exert a synergistic effect on reducing dyslipidemia by inhibiting CD36 expression. Materials and Results: In vitro experiments revealed that a stepwise increase in glyceryl trioleate (TG) or oxidized low-density lipoprotein (ox-LDL) concentrations led to increased lipid-droplet formation (LDF) in macrophages. Silencing receptor CD36, but not the LDL receptor, as well as dapagliflozin/alirocumab therapy significantly attenuated LDF in macrophages. Lipid droplets were transferred from TG or ox-LDL-treated macrophages to untreated macrophages using tunneling nanotubes. Combined dapagliflozin/alirocumab therapy was superior to monotherapy in upregulating lipoprotein lipase activity (LPLa) and suppressing the expression levels of receptor CD36, angiopoietin-4 (ANGPT4), LDF, proinflammatory cytokines, oxidative-stress markers, and PPARγ in macrophages and hepatocytes. This was achieved by downregulating Fyn/Scr/MAPK-family signaling. In vivo, db/db mice were categorized into groups 1 [ db/db + high-fat diet (HFD)]/2 ( db/db + HFD + dapagliflozin)/3 ( db/db + HFD + alirocumab)/4 ( db/db + HFD + combined dapagliflozin/alirocumab). After 12 weeks of HFD feeding, circulatory levels of ANGPTL4, TG, total cholesterol, and LDL, as well as the number of aortic atheromas, inflammatory cell count, aortic tension, and circulatory proinflammatory cytokine levels were all significantly higher in group 1, while these were significantly reversed in groups 2/3 and further significantly reversed in group 4. Meanwhile, body weight, blood sugar, HB1AC, and LPLa exhibited an opposite pattern among the groups (all P < 0.0001). Conclusion: Receptor CD36 plays a critical role in LDF/atherogenic dyslipidemia, which were synergistically suppressed by combined dapagliflozin-alirocumab therapy.