Fenofibrate lowers lipid accumulation in myotubes by modulating the PPARα/AMPK/FoxO1/ATGL pathway.

Abstract

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.

• Authors: Wei-Lu Chen, Yu-Lin Chen, Yu-Ming Chiang, Shyang-Guang Wang, Horng-Mo Lee
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 84 Issue 4 Pg. 522-31 (Aug 15 2012) ISSN: 1873-2968 [Electronic] England
• PMID: 22687626 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Forkhead Box Protein O1
• Forkhead Transcription Factors
• Foxo1 protein, mouse
• Hypolipidemic Agents
• PPAR alpha
• AMP-Activated Protein Kinases
• Lipase
• PNPLA2 protein, mouse
• Acetyl-CoA Carboxylase
• Fenofibrate

Topics

• AMP-Activated Protein Kinases (physiology)
• Acetyl-CoA Carboxylase (metabolism)
• Animals
• Cell Line
• Cell Nucleus (metabolism)
• Cytosol (metabolism)
• Fenofibrate (pharmacology)
• Forkhead Box Protein O1
• Forkhead Transcription Factors (metabolism, physiology)
• Hypolipidemic Agents (pharmacology)
• Lipase (genetics, physiology)
• Lipid Metabolism
• Male
• Mice
• Muscle Fibers, Skeletal (metabolism)
• PPAR alpha (physiology)
• Phosphorylation
• Promoter Regions, Genetic
• Protein Binding
• Protein Transport
• Signal Transduction