Effects of a high-fat diet on energy metabolism and ROS production in rat liver.
OBJECTIVE
A high-fat diet affects liver metabolism, leading to steatosis, a complex disorder related to insulin resistance and mitochondrial alterations. Steatosis is still poorly understood since diverse effects have been reported, depending on the different experimental models used.


METHODS
We hereby report the effects of an 8 week high-fat diet on liver energy metabolism in a rat model, investigated in both isolated mitochondria and hepatocytes.


RESULTS
Liver mass was unchanged but lipid content and composition were markedly affected. State-3 mitochondrial oxidative phosphorylation was inhibited, contrasting with unaffected cytochrome content. Oxidative phosphorylation stoichiometry was unaffected, as were ATPase and adenine nucleotide translocator proteins and mRNAs. Mitochondrial acylcarnitine-related H(2)O(2) production was substantially higher and the mitochondrial quinone pool was smaller and more reduced. Cellular consequences of these mitochondrial alterations were investigated in perifused, freshly isolated hepatocytes. Ketogenesis and fatty acid-dependent respiration were lower, indicating a lower β-oxidation rate contrasting with higher RNA contents of CD36, FABP, CPT-1, and AcylCoA dehydrogenases. Concomitantly, the cellular redox state was more reduced in the mitochondrial matrix but more oxidized in the cytosol: these opposing changes are in agreement with a significantly higher in situ mitochondrial proton motive force.


CONCLUSIONS
A high-fat diet results in both a decrease in mitochondrial quinone pool and a profound modification in mitochondrial lipid composition. These changes appear to play a key role in the resulting inhibition of fatty acid oxidation and of mitochondrial oxidative-phosphorylation associated with an increased mitochondrial ROS production. Mitochondrial quinone pool could have prospects as a crucial event, potentially leading to interesting therapeutic perspectives.
Inserm, U884, Grenoble, F-38041 France. Guillaume.vial@ujf-grenoble.fr
Guillaume
G
Vial
Hervé
H
Dubouchaud
Karine
K
Couturier
Cécile
C
Cottet-Rousselle
Nellie
N
Taleux
Anne
A
Athias
Anne
A
Galinier
Louis
L
Casteilla
Xavier M
XM
Leverve
D000818:Animals; D001823:Body Composition; D004041:Dietary Fats / Q000008:administration & dosage*; D004579:Electron Transport; D004734:Energy Metabolism; D022781:Hepatocytes / Q000378:metabolism; D008055:Lipids / Q000032:analysis; D008099:Liver / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D053078:Membrane Potential, Mitochondrial; D008930:Mitochondria, Liver / Q000737:chemistry; D010085:Oxidative Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014158:Transcription, Genetic
D004041:Dietary Fats; D008055:Lipids; D017382:Reactive Oxygen Species