Global and hepatocyte-specific ablation of Bmal1 induces hyperlipidaemia and enhances atherosclerosis

• Published in: Nature communications Vol. 7; no. 1; p. 13011
• Main Authors: Pan, Xiaoyue, Bradfield, Christopher A., Hussain, M. Mahmood
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10-10-2016; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 14; 42; 631/443/1338/2100; 631/443/592/75/593/2100; 64; 64/60; 692/4019/592/75/2099; 692/699/75/2099; Ablation; Animals; Apolipoproteins E - deficiency; Apolipoproteins E - metabolism; ARNTL Transcription Factors - deficiency; ARNTL Transcription Factors - metabolism; Atherosclerosis; Atherosclerosis - complications; Atherosclerosis - metabolism; ATP Binding Cassette Transporter, Subfamily G, Member 5 - genetics; ATP Binding Cassette Transporter, Subfamily G, Member 5 - metabolism; Bile; Cardiac arrhythmia; Cell Line, Tumor; Cholesterol; Cholesterol - metabolism; Circadian rhythm; GATA4 Transcription Factor - metabolism; Hepatocytes - metabolism; Humanities and Social Sciences; Humans; Hyperlipidemias - complications; Hyperlipidemias - metabolism; Lipid Metabolism; Lipids; Lipoproteins; Lipoproteins - biosynthesis; Lipoproteins - genetics; Lipoproteins - metabolism; Liver; Liver - metabolism; Medical research; Mice, Inbred C57BL; Models, Biological; multidisciplinary; Organ Specificity; Plasma; Promoter Regions, Genetic - genetics; Protein Binding; Proteins; Receptors, Cytoplasmic and Nuclear - metabolism; Science; Science (multidisciplinary); Transcription factors; New York; United States > US
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13011

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.
Bmal1 is a key transcription factor that controls rhythmicity of diverse biological functions. Here, Pan
et al
. show that Bmal1 deficiency in mice increases lipoprotein secretion and reduces cholesterol excretion to bile, and decipher the molecular mechanisms underlying hyperlipidaemia and atherosclerosis promoted by the lack of Bmal1.