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The Sirt1 activator SRT3025 provides atheroprotection in Apoe-/- mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression.
- Source :
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European heart journal [Eur Heart J] 2015 Jan 01; Vol. 36 (1), pp. 51-9. Date of Electronic Publication: 2014 Mar 06. - Publication Year :
- 2015
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Abstract
- Aims: The deacetylase sirtuin 1 (Sirt1) exerts beneficial effects on lipid metabolism, but its roles in plasma LDL-cholesterol regulation and atherosclerosis are controversial. Thus, we applied the pharmacological Sirt1 activator SRT3025 in a mouse model of atherosclerosis and in hepatocyte culture.<br />Methods and Results: Apolipoprotein E-deficient (Apoe(-/-)) mice were fed a high-cholesterol diet (1.25% w/w) supplemented with SRT3025 (3.18 g kg(-1) diet) for 12 weeks. In vitro, the drug activated wild-type Sirt1 protein, but not the activation-resistant Sirt1 mutant; in vivo, it increased deacetylation of hepatic p65 and skeletal muscle Foxo1. SRT3025 treatment decreased plasma levels of LDL-cholesterol and total cholesterol and reduced atherosclerosis. Drug treatment did not change mRNA expression of hepatic LDL receptor (Ldlr) and proprotein convertase subtilisin/kexin type 9 (Pcsk9), but increased their protein expression indicating post-translational effects. Consistent with hepatocyte Ldlr and Pcsk9 accumulation, we found reduced plasma levels of Pcsk9 after pharmacological Sirt1 activation. In vitro administration of SRT3025 to cultured AML12 hepatocytes attenuated Pcsk9 secretion and its binding to Ldlr, thereby reducing Pcsk9-mediated Ldlr degradation and increasing Ldlr expression and LDL uptake. Co-administration of exogenous Pcsk9 with SRT3025 blunted these effects. Sirt1 activation with SRT3025 in Ldlr(-/-) mice reduced neither plasma Pcsk9, nor LDL-cholesterol levels, nor atherosclerosis.<br />Conclusion: We identify reduction in Pcsk9 secretion as a novel effect of Sirt1 activity and uncover Ldlr as a prerequisite for Sirt1-mediated atheroprotection in mice. Pharmacological activation of Sirt1 appears promising to be tested in patients for its effects on plasma Pcsk9, LDL-cholesterol, and atherosclerosis.<br /> (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.)
- Subjects :
- Anilides pharmacology
Animals
Anticholesteremic Agents pharmacology
Apolipoproteins E deficiency
Cells, Cultured
Cholesterol, LDL metabolism
Enzyme Inhibitors pharmacology
Hepatocytes drug effects
In Vitro Techniques
Male
Mice, Inbred C57BL
Proprotein Convertase 9
RNA, Messenger metabolism
Receptors, LDL drug effects
Thiazoles pharmacology
Arteriosclerosis prevention & control
Hepatocytes metabolism
Proprotein Convertases metabolism
Receptors, LDL metabolism
Serine Endopeptidases metabolism
Sirtuin 1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1522-9645
- Volume :
- 36
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- European heart journal
- Publication Type :
- Academic Journal
- Accession number :
- 24603306
- Full Text :
- https://doi.org/10.1093/eurheartj/ehu095