TY - JOUR
T1 - Fluvastatin activates sirtuin 6 to regulate sterol regulatory element-binding proteins and AMP-activated protein kinase in HepG2 cells
AU - Kim, Ji Hye
AU - Lee, Jun Mi
AU - Kim, Jong Hoon
AU - Kim, Kwang Rok
N1 - Funding Information:
This project was supported by Korea Research Institute of Chemical Technology. The chemicals used in this study were provided by Korea Chemical Bank (http://www.chembank.org/). We thank the members of innovative target research center in KRICT and stem cell and tissues regeneration lab in Korea University.
Funding Information:
This project was supported by Korea Research Institute of Chemical Technology . The chemicals used in this study were provided by Korea Chemical Bank ( http://www.chembank.org/ ). We thank the members of innovative target research center in KRICT and stem cell and tissues regeneration lab in Korea University.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/9/10
Y1 - 2018/9/10
N2 - 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.
AB - 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.
KW - AMP-Activated protein kinaseα
KW - Fluvastatin
KW - Nonalcoholic fatty liver disease
KW - SIRT6
KW - SREBP-1
UR - http://www.scopus.com/inward/record.url?scp=85050851678&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2018.07.057
DO - 10.1016/j.bbrc.2018.07.057
M3 - Article
C2 - 30078674
AN - SCOPUS:85050851678
VL - 503
SP - 1415
EP - 1421
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 3
ER -
