Early intermittent cholesterol exposure accelerates atherosclerosis: an oscillating amplifier calling for preemptive control

A recent publication in Nature 1 identi fi ed early intermittent hyperlipidemia as a new determinant of atherosclerosis driving an altered phenotype of arterial-resident macrophages with defects in autophagy-and efferocytosis-related pathways. These intriguing fi ndings infer the need for preemptive control of cholesterol already at younger age to prevent and limit atherosclerosis. Morespeci fi cally, to assess early cholesterol exposure, Takaoka et al. initiated dietary intervention at 6 weeks of age as compared to “ traditional ” models where hyperlipidemia is induced after 8 weeks. Intriguingly, they found that compared to LDLR − / − mice fed a continuous Western diet (WD), early intermittent hyperlipidemia signi fi cantly accelerated atherosclerotic plaque development in both sexes (Fig. 1). To unravel mechanistic cues underlying the effect of early intermittent hyperlipidemia, they performed RNA-sequencing of plaque-bearing aortae in male LDLR − / − mice fed either continuous (cWD) or intermittent WD (iWD) for 3 weeks, with a particular focus on macrophages. Remarkably, the analysis revealed an altered homeostatic phenotype of resident-like arterial macrophages, which failed to acquire functions rendering them atheroprotective upon early intermittent hyperlipidemia. This fi nding is in line with another recent publication describing an acceleration of atherosclerosis in LDLR − / − mice fed an early alternating high-fat diet as compared to a late continuous HFD for 8 weeks. 2 More speci fi cally, RNA sequencing of the aorta in these mice revealed an alteration of neutrophil reprogramming upon early exposure and alternating