Health aspects of oxidized dietary fats - Oxidation in Foods and Beverages and Antioxidant Applications - page 155

(McGarry and Brown, 1997; Brass, 2002; Steiber et al., 2004). As both starva-
tion and clofibrate treatment lead to an activation of PPAR, a transcription
factor belonging to the nuclear hormone receptor superfamily (Schoonjans et al.,
1996), we have recently raised the hypothesis that activation of this nuclear
receptor is responsible for the increased liver carnitine concentrations observed
in those studies. Indeed, a study in our group revealed for the first time a
marked, about 8-fold increase in the hepatic mRNA content of novel organic
cation transporter 2 (OCTN2) in the liver of rats treated with the PPAR agonist
clofibrate (Luci et al., 2006b). OCTN2 is the physiologically most important
carnitine transporter, operating for the reabsorption of carnitine from the urine as
well as playing a major role in tissue distribution. Subsequent studies in PPAR-
knockout mice further demonstrated that transcriptional up-regulation of hepatic
OCTN2 by fasting or treatment with PPAR agonist WY-14,643 is dependent
on PPAR (van Vlies et al., 2007; Koch et al., 2008). In addition, studies in rats
and pigs showed that OCTN2 is induced by fasting or clofibrate also in several
other tissues with abundant PPAR expression including kidney, skeletal
muscle, heart, and small intestine (Ringseis et al., 2007d; 2008a; 2008b; 2008c;
Luci et al., 2008).
Besides cellular carnitine uptake, evidence has been provided to suggest that
carnitine biosynthesis is also regulated by PPAR; e.g., studies in PPAR-
knockout mice and corresponding wild-type mice showed that treatment with
the PPAR agonist WY-14,643 stimulates the transcription of enzymes involved
in carnitine biosynthesis, trimethyllysine dioxygenase (TMLD), 4-N-trimethyl-
aminobutyraldehyde dehydrogenase (TMABA-DH) and -butyrobetaine
dioxygenase (BBD) only in the liver of wild-type (van Vlies et al., 2007; Koch
et al., 2008). This indicates that transcriptional regulation of those genes is also
mediated by PPAR. Other studies revealed that PPAR-knockout mice had
markedly lower plasma and tissue levels of methionine and -ketoglutarate,
which serve as biosynthetic precursors and enzymatic cofactors (Vaz and
Wanders, 2002), respectively, for carnitine synthesis, when compared to wild-
type mice (Makowski et al., 2009). Collectively, these observations in PPAR-
null mice clearly show that genes encoding proteins involved in carnitine uptake
and carnitine biosynthesis are transcriptionally regulated by PPAR.
Since oxidized fats are also capable of activating PPAR, a recent study has
investigated the effect of oxidized fat on tissue carnitine concentrations and on
expression of genes involved in carnitine homeostasis (Koch et al., 2007a). The
oxidized fat used in this study (Koch et al., 2007a) was prepared by heating
sunflower oil at a relatively low temperature (60 ëC) for a long period. Such fats
usually contain relatively high concentrations of primary lipid peroxidation
products including 9-HODE, 13-HODE and 13-HPODE, which are very potent
PPAR agonists (KÈnig and Eder, 2006; Delerive et al., 2000; Mishra et al.,
2004; SÈ lzle et al., 2004). The study from Koch et al. (2007a) showed that
treatment of rats with such an oxidized fat causes the same alterations as
observed with the administration of the PPAR agonist clofibrate (Luci et al.,
2006b; Ringseis et al., 2007d; 2008b), namely increased hepatic mRNA