Fluvastatin activates sirtuin 6 to regulate sterol regulatory element-binding proteins and AMP-activated protein kinase in HepG2 cells

Ji Hye Kim, Jun Mi Lee, Jong-Hoon Kim, Kwang Rok Kim

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Sirtuins, a family of NAD+-dependent deacetylase enzymes, have been identified as mammalian homologs of yeast silent information regulator 2 (SIR2). Sirtuin 6 (SIRT6) plays important roles in cell homeostasis, DNA damage repair, cancer suppression, and aging. SIRT6 overexpression improves metabolic diseases, such as hypercholesterolemia, cholesterol-related disease, and type 2 diabetes via AMP-activated protein kinase (AMPK) activation. SIRT6 is abundant in the liver and is a crucial target for patients with liver steatosis. Compounds for drug repositioning were screened to identify potential SIRT6 activators, and fluvastatin, a synthetic inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase that reduces cholesterol synthesis, was identified to activate SIRT6. When HepG2 cells were treated with fluvastatin, the expression of SIRT6 and phosphorylation of sterol regulatory element-binding protein (SREBP)-1 and AMPKα which is regulated by SIRT6, increased. In this study, we examined the mechanism underlying cholesterol regulation by fluvastatin via SREBP-1 and AMPKα pathway and suggested that fluvastatin is an SIRT6 activator that regulates cholesterol homeostasis and fatty liver disease.

Original languageEnglish
Pages (from-to)1415-1421
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume503
Issue number3
DOIs
Publication statusPublished - 2018 Sep 10

Keywords

  • AMP-Activated protein kinaseα
  • Fluvastatin
  • Nonalcoholic fatty liver disease
  • SIRT6
  • SREBP-1

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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