Serum lipidomics in low-density lipoprotein receptor (LDLr) deficient mice on chow diet or Western-type Diet (WTD)

Aims: A hallmark of advanced atherosclerosis is inadequate
immunosuppression by regulatory T (Treg) cells inside atherosclerotic
lesions. Dyslipidemia has been suggested to alter Treg cell migration by
affecting the expression of specific membrane proteins, thereby decreasing
Treg cell migration towards atherosclerotic lesions. Besides membrane
proteins, cellular metabolism has been shown to be a crucial factor in
Treg cell migration. We aimed to determine whether dyslipidemia
contributes to altered migration of Treg cells, in part, by affecting
cellular metabolism. Methods and results: Dyslipidemia was induced by
feeding Ldlr-/- mice a Western-type diet for 16-20 weeks and intrinsic
changes in Treg cells affecting their migration and metabolism were
examined. Dyslipidemia was associated with altered mTORC2 signaling in
Treg cells, decreased expression of membrane proteins involved in
migration, including CD62L, CCR7 and S1Pr1, and decreased Treg cell
migration towards lymph nodes. Furthermore, we discovered that
diet-induced dyslipidemia inhibited mTORC1 signaling, induced PPARδ
activation and increased fatty acid (FA) oxidation in Treg cells.
Moreover, mass-spectrometry analysis of serum from Ldlr-/- mice with
normolipidemia or dyslipidemia showed increases in multiple PPARδ ligands
during dyslipidemia. Treatment with a synthetic PPARδ agonist increased
the migratory capacity of Treg cells in vitro and in vivo in an FA
oxidation dependent manner. Furthermore, diet-induced dyslipidemia
actually enhanced Treg cell migration into the inflamed peritoneum and
into atherosclerotic lesions in vitro. Conclusions: Altogether, our
findings implicate that dyslipidemia does not contribute to
atherosclerosis by impairing Treg cell migration as dyslipidemia
associated with an effector-like migratory phenotype in Treg cells.