Dyslipidemia increases CCL2 production via a mTORC1-FOXK1 pathway.
Jasper, Hsuan-Chieh   (University of Washington)
Mentor: Kanter, Jenny
Atherosclerosis is a chronic inflammatory disease in which macrophages perpetually infiltrate the artery walls. Macrophages are potent mediators of the inflammatory response in cardiovascular disease (CVD) and are also responsible for much of the physiological response to insult. Diabetes results in a 2- 10 fold increased risk of CVD, but the underlying mechanisms remain yet to be elucidated. Diabetes is commonly associated with diabetic dyslipidemia, which has a characteristic profile of elevated plasma triglycerides and triglyceride-rich lipoproteins. In this work, we investigate the involvement of the mTOR (mammalian target of rapamycin)-FOXK1 pathway and its role in lipid-induced elevation of Ccl2 (C-C chemokine ligand 2) expression. CCL2 is a chemokine heavily involved in macrophage recruitment. RT-PCR showed that thioglycolate-elicited macrophages which were stimulated with acetylated lowdensity lipoprotein (acLDL) showed a 2-fold increase in Ccl2 expression as compared to vehicle, an effect which was completely suppressed by inhibition of mTORC1 (mTOR Complex 1) by rapamycin treatment. Il1b expression was not upregulated in response to acLDL. Similarly, LPS-induced expression of Ccl2, but not Il1b, was sensitive to rapamycin. Recent research has also linked Forkhead box K1 (FOXK1), a downstream target of the mTORC1 pathway, to regulation of Ccl2 expression. Dyslipidemia activates the mTORC1 axis via phosphorylation, which in turn dephosphorylates FOXK1, resulting in upregulation of Ccl2 expression. Using BMDMs (bone marrow derived macrophages) treated with FOXK1 targeted siRNA, we were able to knockdown FOXK1 expression and investigate its effects on Ccl2 expression. Our findings implicate mTORC1-FOXK1 as a novel regulatory pathway of Ccl2 expression which can be activated by dyslipidemia. These findings establish a potential axis linking diabetes-induced dyslipidemia and chronic inflammation.