Fenofibrate simultaneously induces hepatic fatty acid oxidation, synthesis, and elongation in mice.
A growing body of evidence indicates that peroxisome proliferator-activated receptor alpha (PPARalpha) not merely serves as a transcriptional regulator of fatty acid catabolism but also exerts a much broader role in hepatic lipid metabolism. We determined adaptations in hepatic lipid metabolism and related aspects of carbohydrate metabolism upon treatment of C57Bl/6 mice with the PPARalpha agonist fenofibrate. Stable isotope procedures were applied to assess hepatic fatty acid synthesis, fatty acid elongation, and carbohydrate metabolism. Fenofibrate treatment strongly induced hepatic de novo lipogenesis and chain elongation (+/-300, 150, and 600% for C16:0, C18:0, and C18:1 synthesis, respectively) in parallel with an increased expression of lipogenic genes. The lipogenic induction in fenofibrate-treated mice was found to depend on sterol regulatory element-binding protein 1c (SREBP-1c) but not carbohydrate response element-binding protein (ChREBP). Fenofibrate treatment resulted in a reduced contribution of glycolysis to acetyl-CoA production, whereas the cycling of glucose 6-phosphate through the pentose phosphate pathway presumably was enhanced. Altogether, our data indicate that beta-oxidation and lipogenesis are induced simultaneously upon fenofibrate treatment. These observations may reflect a physiological mechanism by which PPARalpha and SREBP-1c collectively ensure proper handling of fatty acids to protect the liver against cytotoxic damage.
Oosterveer
Maaike H
MH
Department of Pediatrics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands. M.H.Oosterveer@med.umcg.nl
Grefhorst
Aldo
A
van Dijk
Theo H
TH
Havinga
Rick
R
Staels
Bart
B
Kuipers
Folkert
F
Groen
Albert K
AK
Reijngoud
Dirk-Jan
DJ
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology*; D019298:Glucose-6-Phosphate / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism*; D047493:PPAR alpha / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005227:Fatty Acids; D000960:Hypolipidemic Agents; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D047493:PPAR alpha; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D019298:Glucose-6-Phosphate; D010100:Oxygen; D011345:Fenofibrate