Abstract 574: Whole Body and Hepatocyte-specific Deletion of Bmal1 Induces Hyperlipidemia and Enhances Atherosclerosis
The aberrant accumulation of lipids in the plasma is associated with high incidence of atherosclerosis. Plasma lipids exhibit diurnal variations. Diurnal rhythms are controlled by two major transcription factors, Clock and Bmal1. Previously, we have shown that expression of a Clock mutant protein predisposes mice to hyperlipidemia and atherosclerosis. Here we show that the complete and liver-specific ablation of Bmal1 gene expression in Apoe-/- mice promotes hyperlipidemia and atherosclerosis. We observed that Bmal1 deficiency increases of microsomal triglyceride transfer protein (MTP) expression. Molecular studies indicated that Bmal1 deficiency decreases the expression of small heterodimer partner (SHP), a repressor MTP, to increase MTP expression and hepatic lipoprotein production. The effect of Bmal1 deficiency on MTP can be circumvented by the hepatic over expression of SHP. Over expression of SHP in the liver-specific Bmal1 deficient Apoe-/- mice reduced atherosclerosis and plasma lipids. These studies show that Bmal1 regulates hepatic lipoprotein production by regulating SHP. Deregulation of these circadian regulatory mechanisms and physiologic pathways predisposes mice to hyperlipidemia and atherosclerosis.
Author Disclosures: X. Pan: None. M.M. Hussain: None.
- © 2015 by American Heart Association, Inc.