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J. Biol. Chem., Vol. 278, Issue 33, 30525-30533, August 15, 2003

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Changed Energy State and Increased Mitochondrial -Oxidation Rate in Liver of Rats Associated with Lowered Proton Electrochemical Potential and Stimulated Uncoupling Protein 2 (UCP-2) Expression

EVIDENCE FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR- INDEPENDENT INDUCTION OF UCP-2 EXPRESSION^*

Hans J. Grav , Karl J. Tronstad , Oddrun A. Gudbrandsen , Kjetil Berge , Kari E. Fladmark ¶, Tom C. Martinsen ||, Helge Waldum ||, Hege Wergedahl  and Rolf K. Berge  **

From the Institute for Nutrition Research, University of Oslo, N-0316 Oslo, Norway, the Institute of Medicine, Section of Medical Biochemistry, Haukeland University Hospital, N-5021 Bergen, Norway, the ^¶Department of Anatomy and Cell Biology, University of Bergen, Årstadveien 19, N-5009 Bergen, Norway, and the ^||Department of Intra-abdominal Diseases, Norwegian University of Science and Technology, N-7491 Trondheim, Norway

Lowering of plasma triglyceride levels by hypolipidemic agents is caused by a shift in the liver cellular metabolism, which become poised toward peroxisome proliferator-activated receptor (PPAR) -regulated fatty acid catabolism in mitochondria. After dietary treatment of rats with the hypolipidemic, modified fatty acid, tetradecylthioacetic acid (TTA), the energy state parameters of the liver were altered at the tissue, cell, and mitochondrial levels. Thus, the hepatic phosphate potential, energy charge, and respiratory control coefficients were lowered, whereas rates of oxygen uptake, oxidation of pyridine nucleotide redox pairs, -oxidation, and ketogenesis were elevated. Moderate uncoupling of mitochondria from TTA-treated rats was confirmed, as the proton electrochemical potential (p) was 15% lower than controls. The change affected the component only, leaving the pH component unaltered, suggesting that TTA causes induction of electrogenic ion transport rather than electrophoretic fatty acid activity. TTA treatment induced expression of hepatic uncoupling protein 2 (UCP-2) in rats as well as in wild type and PPAR-deficient mice, accompanied by a decreased double bond index of the mitochondrial membrane lipids. However, changes of mitochondrial fatty acid composition did not seem to be related to the effects on mitochondrial energy conductance. As TTA activates PPAR, we discuss how this subtype might compensate for deficiency of PPAR. The overall changes recorded were moderate, making it likely that liver metabolism can maintain its function within the confines of its physiological regulatory framework where challenged by a hypolipemic agent such as TTA, as well as others.

Received for publication, April 2, 2003

^* This work was supported by the Research Council of Norwegian, the University of Bergen, and the Norwegian Cancer Society. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Institute of Medicine, Section of Medical Biochemistry, Haukeland University Hospital, N-5021 Bergen, Norway. Tel.: 47-55973098; Fax: 47-55973115; E-mail: rolf.berge{at}med.uib.no.

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