Clocks and Cholesterol: Co-agonists in Cardiovascular Disease?

Circadian (i.e. 24-hour) rhythms regulate much of our physiology, a under HFD compared to Ldlr −/− single mutants under entrained regulation that is supported by rhythmicity in individual cells of the body. Maintenance of cellular rhythms as well as proper coordination of circadian clocks across different tissues is increasingly recognized to be important for metabolic health and in disease prevention (Roenneberg and Merrow, 2016). Long term follow up of rotating night shift workers strongly supports a link between circadian rhythm disturbance and coronary disease (Vetter et al., 2016). With a growing interest in what “zietgebers”—or time-givers—influence our internal 24-h clock, the study by Akashi et al. in this issue of EBioMedicine starts to address the question as to what extent the link between metabolism and circadian rhythmicity is bidirectional in the context of cardiovascular disease (Akashi et al., 2017-in this issue). Using a mouse model of human familial hypercholesterolemia, the authors reveal that ablation of the low density lipoprotein receptor (LDLR) itself induces circadian abnormalities that may further exacerbate the phenotype expected from loss of LDLR alone. First addressed for its potential role in familial hypersholesterolemia almost 30 years ago (Francke et al., 1984), the LDLR is a cell surfaceassociated protein that binds to and uptakes a variety of cholesterolcontaining molecules. Specifically, its interactions include those with apolipoprotein B100 and apolipoprotein E, both of which contribute to the phospholipid component of low density lipoprotein (LDL) or very low density lipoprotein (VLDL) cholesterol transport particles, respectively. Thus, the LDLR serves as a primary mechanism of cholesterol transport in vivo. Using an Ldlr knockout model (Ldlr) which has an elevated serum cholesterol (200–400 mg/dL under normal diet and N2000 mg/dL under high fat diet [HFD] feeding conditions), Akashi et al. reveal that severe hypercholesterolemia in Ldlr −/− mice, induces a significant increase in period length under “free-running” (24-h constant dark/DD) conditions compared to WT controls on HFD. Furthermore, Ldlr −/− mice fed a HFD show a bimodal activity pattern of activity in free running conditions. To determine whether circadian disruption itself exacerbates the effects of the loss of LDLR at the level of hypercholesterolemia-induced arteriosclerosis, Akashi et al. crossedmicemutant for the circadian gene Period2 (mPer2) (Zheng et al., 1999) with Ldlr −/− mice (Ldlr −/− Per2m/m). Using the double Ldlr−/− Per2m/mmice, the authors reveal that HFD produces an accelerated arteriosclerosis phenotype, with double knockout mice having larger aortic lesions slightly earlier