Hypercholesterolemia Causes Circadian Dysfunction: A Potential Risk Factor for Cardiovascular Disease

Hypercholesterolemia is a well-known risk factor for a wide range of diseases in developed countries. Here, we report that mice lacking functional LDLR (low density lipoprotein receptor), an animal model of human familial hypercholesterolemia, show circadian abnormalities. In free running behavioral experiments in constant darkness, these mice showed a prolonged active phase and distinctly bimodal rhythms. Even when the circadian rhythms were entrained by light and dark cycles, these mice showed a significant attenuation of behavioral onset intensity at the start of the dark period. Further, we hypothesized that the combination of hypercholesterolemia and circadian abnormalities may affect cardiovascular disease progression. To examine this possibility, we generated LDLR-deficient mice with impaired circadian rhythms by simultaneously introducing a mutation into Period2, a core clock gene, and found that these mice showed a significant enlargement of artery plaque area with an increase in inflammatory cytokine IL-6 levels. These results suggest that circadian dysfunction may be associated with the development or progression of cardiovascular diseases. •Mice lacking LDLR (low density lipoprotein receptor), a mouse model for hypercholesterolemia, show circadian abnormalities.•LDLR-deficient mice with a mutation in Period2, a core clock gene, show a significant enlargement of artery plaque area.•Per2 mutation-induced increase in plasma inflammatory cytokines may cause modification of arteriosclerosis. Hypercholesterolemia is a common pathology in advanced countries, occurring in 10% to 30% of the population. Here, we report that mice lacking LDLR (low density lipoprotein receptor), an animal model for hypercholesterolemia, experienced chronic circadian abnormalities. Further, we found that LDLR-deficient mice with a mutation in Period2, a clock gene, showed a significant enlargement of artery plaque area. Together, our findings indicate that hypercholesterolemia induces circadian abnormalities, leading to a decline in the quality of social life and an increase in the risk of circadian-related diseases, and that circadian dysfunction might affect the development or progression of hypercholesterolemia-related diseases.