Fluvastatin activates sirtuin 6 to regulate sterol regulatory element-binding proteins and AMP-activated protein kinase in HepG2 cells
- Division of Innovative Target Research Center, Korea Research Institute of Chemical Technology, Daejeon, 305-343, South (Korea, Republic of)
- Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 136-713, South (Korea, Republic of)
Highlights: • Effects of fluvastatin in human hepatocytes via SIRT6 activation were investigated. • Fluvastatin plays the role of an SIRT6 activator. • Fluvastatin can be used as a new drug for patients with liver steatosis. • Fluvastatin inhibited lipid synthesis by regulating SREBP1 via LKB1/AMPK pathway. Sirtuins, a family of NAD{sup +}-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.
- OSTI ID:
- 23105570
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 503, Issue 3; Other Information: Copyright (c) 2018 Elsevier Inc. All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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