Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice. J Biol Chem 2003 Jul 25;278(30):27997-8004
Date
06/07/2003Pubmed ID
12791698DOI
10.1074/jbc.M302140200Scopus ID
2-s2.0-0042847330 (requires institutional sign-in at Scopus site) 251 CitationsAbstract
Proper function of the peroxisome proliferator-activated receptor alpha (PPARalpha) is essential for the regulation of hepatic fatty acid metabolism. Fatty acid levels are increased in liver during the metabolism of ethanol and should activate PPARalpha. However, recent in vitro data showed that ethanol metabolism inhibited the function of PPARalpha. We now report that ethanol feeding impairs fatty acid catabolism in the liver in part via blocking PPARalpha-mediated responses in C57BL/6J mice. Ethanol feeding decreased PPARalpha/retinoid X receptor alpha binding in electrophoretic mobility shift assay of liver nuclear extracts. mRNAs for PPAR-regulated genes were reduced (long chain and medium chain acyl-CoA dehydrogenases) or failed to be induced (acyl-CoA oxidase, liver carnitine palmitoyl-CoA transferase, very long chain acyl-CoA synthetase, very long chain acyl-CoA dehydrogenase) in livers of the ethanol-fed animals, and ethanol feeding did not increase the rate of fatty acid beta-oxidation. Wy14,643, a PPARalpha agonist, restored the DNA binding activity of PPARalpha/retinoid X receptor alpha, induced mRNA levels of PPARalpha target genes, stimulated the rate of fatty acid beta-oxidation, and prevented fatty liver in ethanol-fed animals. Impairment of PPARalpha function during ethanol consumption contributes to the development of alcoholic fatty liver, which can be overcome by Wy14,643.
Author List
Fischer M, You M, Matsumoto M, Crabb DWMESH terms used to index this publication - Major topics in bold
AnimalsCell Line
Cell Nucleus
DNA
Dimerization
Ethanol
Fatty Acids
HL-60 Cells
Humans
K562 Cells
Lipid Metabolism
Liver
Male
Mice
Mice, Inbred C57BL
Oxygen
Peroxisome Proliferators
Protein Binding
Pyrimidines
Rats
Receptors, Cytoplasmic and Nuclear
Reverse Transcriptase Polymerase Chain Reaction
Time Factors
Transcription Factors
Transfection
