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The Sirt1 activator SRT3025 provides atheroprotection in Apoe-/- mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression.

Miranda MX, van Tits LJ, Lohmann C, Arsiwala T, Winnik S, Tailleux A, Stein S, Gomes AP, Suri V, Ellis JL, Lutz TA, Hottiger MO, Sinclair DA, Auwerx J, Schoonjans K, Staels B, Lüscher TF, Matter CM - Eur. Heart J. (2014)

Bottom Line: 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.Co-administration of exogenous Pcsk9 with SRT3025 blunted these effects.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.

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SRT3025 increases Ldlr expression in AML12 hepatocytes and decreases Pcsk9 in the supernatant. Western blots of Ldlr, Pcsk9, and β-actin in cultured AML12 cells (A) treated with SRT3025 at indicated concentrations for 24 h and (B) incubated with 10 μM SRT3025 for the times indicated. (C) Relative mRNA expression levels of Ldlr and Pcsk9 in AML12 cells after incubation with 10 μM SRT3025 for 24 h. (D) Pcsk9 protein levels in the supernatant of AML12 cells incubated with 10 μM SRT3025 for the times indicated. (E) Pcsk9 immunoprecipiated from AML12 cells incubated with vehicle (Veh, DMSO) or 10 μM SRT3025, and blotted for Ldlr and Pcsk9. Pcsk9, proprotein convertase subtilisin/kexin type 9.
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EHU095F4: SRT3025 increases Ldlr expression in AML12 hepatocytes and decreases Pcsk9 in the supernatant. Western blots of Ldlr, Pcsk9, and β-actin in cultured AML12 cells (A) treated with SRT3025 at indicated concentrations for 24 h and (B) incubated with 10 μM SRT3025 for the times indicated. (C) Relative mRNA expression levels of Ldlr and Pcsk9 in AML12 cells after incubation with 10 μM SRT3025 for 24 h. (D) Pcsk9 protein levels in the supernatant of AML12 cells incubated with 10 μM SRT3025 for the times indicated. (E) Pcsk9 immunoprecipiated from AML12 cells incubated with vehicle (Veh, DMSO) or 10 μM SRT3025, and blotted for Ldlr and Pcsk9. Pcsk9, proprotein convertase subtilisin/kexin type 9.

Mentions: To delineate the mechanisms by which SRT3025 affects Ldlr protein expression, we performed in vitro experiments administering SRT3025 to mouse hepatoma AML12 cells. We observed a concentration- and time-dependent increase in Ldlr and Pcsk9 protein expression upon SRT3025 administration in cell lysates (Figure 4A and B). As observed in vivo, mRNA levels of Ldlr and Pcsk9 were not altered by SRT3025 (Figure 4C), indicating that post-translational effects cause the changes in protein expression.Figure 4


The Sirt1 activator SRT3025 provides atheroprotection in Apoe-/- mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression.

Miranda MX, van Tits LJ, Lohmann C, Arsiwala T, Winnik S, Tailleux A, Stein S, Gomes AP, Suri V, Ellis JL, Lutz TA, Hottiger MO, Sinclair DA, Auwerx J, Schoonjans K, Staels B, Lüscher TF, Matter CM - Eur. Heart J. (2014)

SRT3025 increases Ldlr expression in AML12 hepatocytes and decreases Pcsk9 in the supernatant. Western blots of Ldlr, Pcsk9, and β-actin in cultured AML12 cells (A) treated with SRT3025 at indicated concentrations for 24 h and (B) incubated with 10 μM SRT3025 for the times indicated. (C) Relative mRNA expression levels of Ldlr and Pcsk9 in AML12 cells after incubation with 10 μM SRT3025 for 24 h. (D) Pcsk9 protein levels in the supernatant of AML12 cells incubated with 10 μM SRT3025 for the times indicated. (E) Pcsk9 immunoprecipiated from AML12 cells incubated with vehicle (Veh, DMSO) or 10 μM SRT3025, and blotted for Ldlr and Pcsk9. Pcsk9, proprotein convertase subtilisin/kexin type 9.
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EHU095F4: SRT3025 increases Ldlr expression in AML12 hepatocytes and decreases Pcsk9 in the supernatant. Western blots of Ldlr, Pcsk9, and β-actin in cultured AML12 cells (A) treated with SRT3025 at indicated concentrations for 24 h and (B) incubated with 10 μM SRT3025 for the times indicated. (C) Relative mRNA expression levels of Ldlr and Pcsk9 in AML12 cells after incubation with 10 μM SRT3025 for 24 h. (D) Pcsk9 protein levels in the supernatant of AML12 cells incubated with 10 μM SRT3025 for the times indicated. (E) Pcsk9 immunoprecipiated from AML12 cells incubated with vehicle (Veh, DMSO) or 10 μM SRT3025, and blotted for Ldlr and Pcsk9. Pcsk9, proprotein convertase subtilisin/kexin type 9.
Mentions: To delineate the mechanisms by which SRT3025 affects Ldlr protein expression, we performed in vitro experiments administering SRT3025 to mouse hepatoma AML12 cells. We observed a concentration- and time-dependent increase in Ldlr and Pcsk9 protein expression upon SRT3025 administration in cell lysates (Figure 4A and B). As observed in vivo, mRNA levels of Ldlr and Pcsk9 were not altered by SRT3025 (Figure 4C), indicating that post-translational effects cause the changes in protein expression.Figure 4

Bottom Line: 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.Co-administration of exogenous Pcsk9 with SRT3025 blunted these effects.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research, Institute of Physiology, University of Zurich and University Heart Center, Cardiology, University Hospital Zurich, Raemistrasse 100, 8091 Zurich, Switzerland Zurich Center of Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.

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Related in: MedlinePlus