TY - JOUR
T1 - Fenofibrate lowers lipid accumulation in myotubes by modulating the PPARα/AMPK/FoxO1/ATGL pathway
AU - Chen, Wei Lu
AU - Chen, Yu Lin
AU - Chiang, Yu Ming
AU - Wang, Shyang Guang
AU - Lee, Horng Mo
PY - 2012/8/15
Y1 - 2012/8/15
N2 - Fenofibrate, a fibric acid derivative, is known to possess lipid-lowering effects. Although fenofibrate may activate peroxisome proliferator-activated receptor (PPAR)α and regulate the transcription of several genes, the underlying mechanisms are poorly understood. In this study, we demonstrated that incubation of C2C12 myotubes with fenofibrate increased adipose triglyceride lipase (ATGL) expression and suppressed fatty acid synthase (FAS) level, thereby decreasing intracellular triglyceride accumulation when cells were incubated at high-glucose condition. Fenofibrate increased the phosphorylation of AMP-activated protein kinase (AMPK), which subsequently increased fatty acid β-oxidation. AMPK phosphorylation was reduced by pretreatment with GW9662 (a PPARα inhibitor), suggesting that AMPK may be a downstream effector of PPARα. Pretreatment with compound C (an AMPK inhibitor) or GW9662 blocked fenofibrate-induced ATGL expression and the lipid-lowering effect. Our results suggest that AMPK is as an upstream regulator of ATGL. With further exploration, we demonstrated that fenofibrate stimulated FoxO1 translocation from the cytosol to nuclei by immunefluorescence assay, chromatin immuneprecipitation assay, and reporter assay. Furthermore, oral administration of fenofibrate ameliorated the body weight, visceral fat and serum biochemical indexes in db/db mice. Taken together, our results suggest that the lipid-lowering effect of fenofibrate was achieved by activating PPARα and AMPK signaling pathway that resulted in increasing ATGL expression, lipolysis, and fatty acid β-oxidation.
AB - Fenofibrate, a fibric acid derivative, is known to possess lipid-lowering effects. Although fenofibrate may activate peroxisome proliferator-activated receptor (PPAR)α and regulate the transcription of several genes, the underlying mechanisms are poorly understood. In this study, we demonstrated that incubation of C2C12 myotubes with fenofibrate increased adipose triglyceride lipase (ATGL) expression and suppressed fatty acid synthase (FAS) level, thereby decreasing intracellular triglyceride accumulation when cells were incubated at high-glucose condition. Fenofibrate increased the phosphorylation of AMP-activated protein kinase (AMPK), which subsequently increased fatty acid β-oxidation. AMPK phosphorylation was reduced by pretreatment with GW9662 (a PPARα inhibitor), suggesting that AMPK may be a downstream effector of PPARα. Pretreatment with compound C (an AMPK inhibitor) or GW9662 blocked fenofibrate-induced ATGL expression and the lipid-lowering effect. Our results suggest that AMPK is as an upstream regulator of ATGL. With further exploration, we demonstrated that fenofibrate stimulated FoxO1 translocation from the cytosol to nuclei by immunefluorescence assay, chromatin immuneprecipitation assay, and reporter assay. Furthermore, oral administration of fenofibrate ameliorated the body weight, visceral fat and serum biochemical indexes in db/db mice. Taken together, our results suggest that the lipid-lowering effect of fenofibrate was achieved by activating PPARα and AMPK signaling pathway that resulted in increasing ATGL expression, lipolysis, and fatty acid β-oxidation.
KW - AMP-activated protein kinase
KW - Adipose triglyceride lipase
KW - Fatty acid synthase
KW - Free fatty acid β-oxidation
KW - Lipid metabolism
UR - http://www.scopus.com/inward/record.url?scp=84864116265&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84864116265&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2012.05.022
DO - 10.1016/j.bcp.2012.05.022
M3 - Article
C2 - 22687626
AN - SCOPUS:84864116265
SN - 0006-2952
VL - 84
SP - 522
EP - 531
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 4
ER -