The novel sirt1 activator srt3025 provides atheroprotection through increased hepatic low-density lipoprotein receptor expression

Abstract

Background: Increased plasma low-density lipoprotein (LDL) cholesterol is a driving force of atherosclerosis. Hepatic LDL receptor (LDL-R) expression confers atheroprotection by removing cholesterol from the blood stream. Genetic studies of SIRT1 have predominantly shown to have beneficial effects in metabolic diseases. However, its role in atherosclerosis and lipid metabolism remains controversial. Purpose: We compared the effects of pharmacological SIRT1 activation on lipid metabolism and atherosclerosis in apolipoprotein E knockout (ApoE-/-) and LDL-R knockout (LDL-R-/-) mice. Methods: We placed male ApoE-/- or LDL-R-/- mice on a high-cholesterol diet (1.25% w/w) or the same diet supplemented with the SIRT1 activator SRT3025 (3.18g/kg diet; Sirtris, Cambridge, MA, USA) for 12 weeks and then assessed plasma lipids and cytokines, severity of aortic atherosclerosis, hepatic lipid content and hepatic expression of genes involved in inflammation and lipid homeostasis. In addition, we assessed the effects of SRT3025 on LDL-R expression in hepatic AML12 cells in vitro. Results: ApoE-/- mice treated with SRT3025 showed less atherosclerosis and steato-hepatitis and had lower levels of plasma cholesterol (LDL- and total cholesterol), TNFα, MCP-1, and IL-6 compared with placebo-treated control mice. LDL-R expression was increased 10-fold in drug-treated ApoE-/- mice. Corresponding SRT3025 experiments in LDL-R-/- mice revealed a loss of atheroprotection without a decrease in plasma cholesterol. In vitro SIRT1 activator treatment of hepatic AML12 cells induced LDL-R expression; this increase was abolished after SIRT1 knockdown. Conclusions: Pharmacological SIRT1 activation confers atheroprotection through increased hepatic LDL-R protein expression and decreased plasma LDL cholesterol. Our findings identify induction of hepatic LDL-R expression as a novel downstream effect of SIRT1 activity and highlight the potential of SIRT1 activation as an anti-atherosclerotic strategy.