MiP2005: Session 10
Mitochondrial Physiology Network 10.9: 112 (2005) - download pdf
Rolf K Berge, KJ Tronstad, J Skorve
Inst. Medicine, University of Bergen, Norway. - email@example.com
Much data indicates that lowering of plasma triglyceride levels by hypolipidemic agents is caused by a shift in the liver metabolism, toward peroxisome proliferator activated receptor (PPAR) α regulated fatty acid catabolism in mitochondria. Feeding rats with tetradecylthioacetic acid (TTA) leads to hypolipidemia possibly by increased channeling of fatty acids to mitochondrial fatty acid oxidation at the expense of triacylglyceride synthesis . Our results suggest that a TTA-induced increase in hepatic fatty acid oxidation and ketogenesis drains fatty acids from blood and extrahepatic tissues and that this contributes significantly to the beneficial effects of TTA on fat mass accumulation and peripheral insulin sensitivity . These effects are associated with altered energy state parameters of the liver at the tissue-, cellular, and mitochondrial level . The hepatic phosphate potential, energy charge, and respiratory control coefficients were lowered, while rates of oxygen uptake and oxidation of pyridine nucleotide redox pairs. This is compatible with uncoupling of mitochondria due to increased proton conductance of the inner membrane. Thus, uncoupling activity of TTA was confirmed by measuring the proton electrochemical potential. The data suggested that TTA influences expression and/or activity of electrogenic ion transport systems in the mitochondrial membrane. A candidate protein is uncoupling protein 2 (UCP-2) whose mRNA expression was induced after TTA treatment in rats as well as in wild type and PPARα-deficient mice. TTA also activates the other PPARs (e.g. PPARδ), and this may compensate for the deficiency of PPARα.
1. Berge RK et al. (2002) Curr. Opin. Lipidol. 13: 295-304.
2. Berge RK et al. (2005) Biochimie 87: 15-20.
3. Grav HJ et al. (2003) J. Biol. Chem. 278: 30525-30533.