Abstract 256: Global and Hepatocyte-specific Ablation of Bmal1 Induces Hyperlipidemia and Enhances Atherosclerosis

Abstract

Circadian rhythms controlled by clock genes affect plasma lipids, known risk factors for atherosclerosis. We observed that global ablation of a critical clock gene, Bmal1 , in Apoe –/– and Ldlr –/– mice, and liver-specific ablation of Bmal1 in Apoe –/– (L -Bmal1 –/– Apoe –/– ) mice increases hyperlipidemia and atherosclerosis. In contrast, overexpression of BMAL1 in L-Bmal1 –/– Apoe –/– mice decreases hyperlipidemia and atherosclerosis. Physiologic studies showed that Bmal1 deficiency augments hepatic lipoprotein secretion and diminishes cholesterol excretion to the bile. Molecular studies identified that Bmal1 deficiency reduces expression of Shp, a repressor, and Gata4, an activator. Reductions in Shp increase Mtp expression and lipoprotein production, whereas reductions in Gata4 diminish Abcg5/Abcg8 expression and cholesterol excretion to the bile. SHP expression normalized lipoprotein secretion with no effect on cholesterol excretion to the bile, while GATA4 expression increased cholesterol excretion to the bile and reduced plasma lipids in L-Bmal1 –/– Apoe –/– mice. Taken together, our data indicate that Bmal1 modulates lipoprotein secretion to the plasma and cholesterol excretion to the bile by regulating the expression of Mtp and Abcg5/Abcg8 via Shp and Gata4, and that the loss of Bmal1 promotes hyperlipidemia and atherosclerosis.