Journal
BIOCHEMICAL PHARMACOLOGY
Volume 84, Issue 4, Pages 522-531Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2012.05.022
Keywords
AMP-activated protein kinase; Adipose triglyceride lipase; Fatty acid synthase; Free fatty acid beta-oxidation; Lipid metabolism
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Funding
- National Science Council of Taiwan [NSC99-3112-B-166-001, NSC100-2320-B-166-001]
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Fenofibrate, a flbric acid derivative, is known to possess lipid-lowering effects. Although fenofibrate may activate peroxisome proliferator-activated receptor (PPAR)alpha 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 beta-oxidation. AMPK phosphorylation was reduced by pretreatment with GW9662 (a PPAR alpha inhibitor), suggesting that AMPK may be a downstream effector of PPAR alpha. 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 fenoflbrate 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 PPAR alpha and AMPK signaling pathway that resulted in increasing ATGL expression, lipolysis, and fatty acid beta-oxidation. (C) 2012 Elsevier Inc. All rights reserved.
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