SIRT1 activator E1231 protects from experimental atherosclerosis and lowers plasma cholesterol and triglycerides by enhancing ABCA1 expression

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Epigenetic targets open new hopes for treating atherosclerosis

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When lipid metabolism is completely unbalanced, with an excess of cholesterol, triglycerides (TG), and Low-Density Lipoproteins (LDL) circulating inside arteries, it can cause plaque to build up on artery walls and lead to a risk of clogging. Arteries narrowed by plaque reduce blood flow and oxygen delivery to vital organs, leading to the possibility of severe life-threatening problems such as heart attacks and strokes. This disease is known as atherosclerosis. Progression of the disease is often silent, with no visible symptoms. Nonetheless, the risk of cardiovascular damage is high.
Changing habits or lifestyle, improving diet with a low-fat regimen, and taking lipid-lowering drugs can prevent such complications. Though many treatments exist currently, scientists continue to seek new targets to provide better treatment.
The NAD+-dependent deacetylase Sirtuin-1 (SIRT1), member of the Class III histone deacetylase family, has been studied in-depth for many years in the field of epigenetics, and its biological functions are now quite well characterized. In this article, Tingting Feng emphasizes the role of SIRT1 in the regulation of lipid metabolism. She implemented a High-Throughput Screening assay and identified a new SIRT1 activator – E1231 – from a library of 12,000 compounds.
In-vitro studies on HepG2 and RAW 264.7 cells, combining SPR, Western-blot, sIRNA, and many other techniques, have assessed the high potency of this SIRT1 activator clearly. Animal studies in ApoE-/- mice treated with E1231 have confirmed its capability to reduce atherosclerosis plaque development in-vivo.
Tingting Feng’s study provides solid and convincing data that highlights the clear role of SIRT1 in modulating cholesterol and lipid metabolism. True epigenetic targets, traditionally studied in an oncology context, can also play a key role in regulating metabolic disorders.
This approach allows researchers to move from cancer to cardiovascular disease treatment. Always think outside the box!


Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide-dependent protein deacetylase. Recent studies have demonstrated that enhancing SIRT1 expression or activity may modulate cholesterol and lipid metabolism. However, pharmacological and molecular regulators for SIRT1 are scarce. Here, we aimed to find novel small molecule modulators of SIRT1 to regulate cholesterol and lipid metabolism.
A high-throughput screening assay was established to identify SIRT1 activators. Surface plasmon resonance and immunoprecipitation were performed to confirm the interaction of E1231 with SIRT1. Cholesterol assay was performed to demonstrate the in vitro effect of E1231. The in vivo effect of E1231 was evaluated in experimental models.
E1231, a piperazine 1,4-diamide compound, was identified as a SIRT1 activator with EC50 value of 0.83 μM. E1231 interacted with recombinant human SIRT1 protein and deacetylated liver X receptor-alpha (LXRα). E1231 increased ATP-binding cassette transporter A1 (ABCA1) expression in RAW 264.7 cells dependent on SIRT1 and LXRα. E1231 promoted cholesterol efflux and inhibited lipid accumulation in RAW 264.7 cells via SIRT1 and ABCA1. In the golden hamster hyperlipidemia model, E1231 treatment decreased total cholesterol and triglyceride levels in both serum and the liver, while increased cholesterol content in feces. Moreover, E1231 increased ABCA1 and SIRT1 protein expression in the liver. In ApoE-/- mice, E1231 treatment reduced atherosclerotic plaque development compared with untreated ApoE-/- mice.
We identified a novel SIRT1 activator E1231 and elucidated its beneficial effects on lipid and cholesterol metabolism. Our study suggests that E1231 might be developed as a novel drug for treating atherosclerosis.


Atherosclerosis. 2018 Jul; 274:172-181.

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