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

Wei Lu Chen, Yu Lin Chen, Yu Ming Chiang, Shyang Guang Wang, Horng Mo Lee

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46 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)522-531
Number of pages10
JournalBiochemical Pharmacology
Volume84
Issue number4
DOIs
Publication statusPublished - Aug 15 2012

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Keywords

  • Adipose triglyceride lipase
  • AMP-activated protein kinase
  • Fatty acid synthase
  • Free fatty acid β-oxidation
  • Lipid metabolism

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

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