Global and hepatocyte-specific ablation of Bmal1 induces hyperlipidaemia and enhances atherosclerosis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 27721414.
- Also identified by DOI 10.1038/ncomms13011 and PMC identifier 5062545.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Circadian rhythms controlled by clock genes affect plasma lipids. Here we show that global ablation of Bmal1 in Apoe-/- and Ldlr-/- mice and its liver-specific ablation in Apoe-/- (L-Bmal1-/-Apoe-/-) mice increases, whereas overexpression of BMAL1 in L-Bmal1-/-Apoe-/- and Apoe-/-mice decreases hyperlipidaemia and atherosclerosis. Bmal1 deficiency augments hepatic lipoprotein secretion and diminishes cholesterol excretion to the bile. Further, Bmal1 deficiency reduces expression of Shp and Gata4. Reductions in Shp increase Mtp expression and lipoprotein production, whereas reductions in Gata4 diminish Abcg5/Abcg8 expression and biliary cholesterol excretion. Forced SHP expression normalizes lipoprotein secretion with no effect on biliary cholesterol excretion, while forced GATA4 expression increases cholesterol excretion to the bile and reduces plasma lipids in L-Bmal1-/-Apoe-/- and Apoe-/- mice. Thus, our data indicate that Bmal1 modulates lipoprotein production and biliary cholesterol excretion by regulating the expression of Mtp and Abcg5/Abcg8 via Shp and Gata4.
Medical subject headings
- ARNTL Transcription Factors
- Atherosclerosis
- Hepatocytes
- Hyperlipidemias