Peroxisome proliferator-activated receptors (PPARs) and mitochondria in relation to lifestyle-related diseases
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Obesity is a growing life-style related health problem, and is often accompanied by dyslipidemia, insulin resistance and inflammation. This may in turn lead to hyperinsulinemia, increased risk of non-alcoholic fatty liver disease, type 2 diabetes mellitus and cardiovascular disease. Together, these abnormalities have been clustered into the metabolic syndrome. The present thesis focuses on two modified fatty acids, tetradecylthioacetic acid (TTA) and tetradecylselenoacetic acid (TSA), with a biochemical and mechanistic angle to the description and possible therapeutic options of obesity related disorders and risk factors of the metabolic syndrome and cardiovascular disease. As major regulators of lipid metabolism and their involvement in glucose metabolism and inflammation, the peroxisome proliferatoractivated receptors (PPARs; PPARa, PPARd, PPARg) have been in focus in these studies. We have shown that through increased fatty acid oxidation, TTA may prevent the development of fatty liver induced by tamoxifen, a drug commonly used in patients with breast cancer. Furthermore, TTA had lipid lowering effects in patients with type 2 diabetes mellitus, through mechanisms seeming to involve PPARa and PPAR activation, and increased mitochondrial fatty acid oxidation. The role of PPARa in TTA mediated effects was investigated in PPARa deficient mice, and revealed that TTA was able to stimulate fatty acid oxidation in mice lacking PPARa, indicating that PPARa is involved in but not essential for the lipid lowering effects of TTA. In cell culture PPAR activation studies we confirmed that TTA may stimulate the activity of all PPARs. Moreover, we found that PPARg coactivator (PGC)-1 is a potent PPAR coactivator, and that TTA further induced the PGC-1 mediated coactivation of PPARd. Thus, it seems reasonable to believe that the activity of both PPARa and PPARd, with a substantial contribution of nuclear receptor coactivators, PGC-1 in special, may be conductive to TTA’s mechanism of action. Studies with TSA suggest that it exert potent antioxidant, antiinflammatory and hypolipidemic properties, potentially involving PPAR-related mechanisms. Antioxidants protect against oxidative stress and inflammation, which, in combination with hyperlipidemia, are important mediators of atherogenesis. Based on this, it is tempting to hypothesize that TSA could be an interesting antiatherogenic approach to atherosclerotic disorders. Altogether the present thesis demonstrates that TTA and TSA may have a possible therapeutic potential in obesity related disorders and risk factors of the metabolic syndrome and cardiovascular disease. Their mechanism of action seems to include the action of PPARs, with contribution of nuclear receptor coactivators.
Består avPaper I: Journal of Lipid Research 47(10), Causes and prevention of tamoxifen-induced accumulation of triacylglycerol in rat liver, pp. 2223–2232. Copyright 2006 American Society for Biochemistry and Molecular Biology. All rights reserved. Full-text not available due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1194/jlr.M600148-JLR200
Paper II: Kristian Løvås, Therese H. Røst, Jon Skorve, Rune J. Ulvik, Oddrun A. Gudbrandsen, Pavol Bohov, Andreas J. Wensaas, Arild C. Rustan, Rolf K. Berge, Eystein S. Husebye. Tetradecylthioacetic acid attenuates dyslipidemia in type 2 diabetic patients, possibly by dual PPARa/d activation and increased mitochondrial fatty acid oxidation. Submitted to Diabetologia, April 2008. Preprint.
Paper III: Therese H. Røst, Line L.H. Moi, Kjetil Berge, Bart Staels, Gunnar Mellgren, Rolf K. Berge. The pan-PPAR ligand, tetradecylthioacetic acid, induces hepatic fatty acid oxidation in PPARa-/- mice possibly through stimulation of PGC-1 dependent coactivation of PPARd. Manuscript.
Paper IV: Arteriosclerosis, Thrombosis, and Vascular Biology, 27 (3), Tetradecylselenoacetic Acid, a PPAR Ligand with Antioxidant, Antiinflammatory, and Hypolipidemic Properties, pp. 628-634. Copyright 2007 American Heart Association. All rights reserved. Full-text not available due to publisher restrictions. The published version is available at: http://dx.doi.org/10.1161/01.ATV.0000255950.70774.d5