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

Tingting Feng1, Peng Liu2, Xiao Wang2

  • 1NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100050, China; Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.

Atherosclerosis
|May 23, 2018
PubMed
Abstract

Insights

Researchers discovered E1231, a novel Sirtuin 1 (SIRT1) activator, that effectively modulates cholesterol and lipid metabolism. This compound shows potential for treating atherosclerosis by improving lipid profiles and reducing plaque development.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Sirtuin 1 (SIRT1) is a key NAD+-dependent deacetylase involved in cellular regulation.
  • SIRT1 activity influences cholesterol and lipid metabolism, but specific regulators are limited.
  • Novel small molecules are needed to target SIRT1 for metabolic regulation.

Purpose of the Study:

  • To identify novel small molecule modulators of SIRT1.
  • To investigate the role of these modulators in regulating cholesterol and lipid metabolism.
  • To evaluate the therapeutic potential for metabolic disorders.

Main Methods:

  • High-throughput screening to identify SIRT1 activators.
  • Surface plasmon resonance and immunoprecipitation for interaction confirmation.
  • In vitro and in vivo assays in cell lines and animal models (hamsters, ApoE-/- mice).

Main Results:

  • E1231 identified as a SIRT1 activator (EC50=0.83 μM), interacting with SIRT1 and deacetylating LXRα.
  • E1231 increased ABCA1 expression, promoted cholesterol efflux, and inhibited lipid accumulation in vitro.
  • E1231 reduced serum/liver cholesterol and triglycerides, increased fecal cholesterol, and decreased atherosclerotic plaques in vivo.

Conclusions:

  • E1231 is a novel SIRT1 activator with significant beneficial effects on lipid and cholesterol metabolism.
  • E1231 demonstrates potential as a therapeutic agent for atherosclerosis.
  • Further development of E1231 could offer a new treatment strategy for metabolic diseases.
Keywords:
ABCA1Cholesterol and lipid metabolismLXRαSIRT1

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