Health aspects of oxidized dietary fats - Oxidation in Foods and Beverages and Antioxidant Applications - page 152

temperatures. In addition, the studies from Martin et al. (2000) and Bretillon et
al. (2003) suggest that CFAM, which are also characteristic substances of
oxidized fats, are activators of PPAR too. CFAM are only significantly formed
from the unsaturated 18-carbon fatty acids (C18:1n-9, C18:2n-6, C18:3n-3) in
vegetable oils heated at temperatures above 200 ëC (Sebedio and Grandgirard,
1989; Rojo and Perkins, 1987; Tompkins and Perkins, 2000; Christopoulou and
Perkins, 1989).
The cholesterol-lowering effect of oxidized fat is likely due to inhibition of
transcription of genes involved in cholesterol homeostasis as suggested from a
recent study (Koch et al., 2007b). Cholesterol homeostasis in mammalian cells
is mainly regulated by sterol regulatory element-binding protein (SREBP)-2.
This transcription factor preferentially activates genes involved in cellular chol-
esterol uptake (e.g., LDL receptor) and cholesterol synthesis (e.g., 3-hydroxy-3-
methylglutaryl CoA (HMG-CoA) reductase) (McPherson and Gauthier, 2004;
Horton, 2002). Koch et al. (2007b) demonstrated in rats that administration of
oxidized fat inhibits activation of hepatic SREBP-2 and reduces hepatic
transcript levels of LDL receptor and HMG-CoA reductase genes, both of which
are important for cellular cholesterol uptake and synthesis, respectively. As a
consequence of the reduced expression of these genes in the liver, the
concentrations of cholesterol in liver and plasma are lowered, which explains the
reduction of cholesterol concentrations in liver and plasma by oxidized fats.
Inhibition of SREBP-2 activation by oxidized fat is likely mediated by an up-
regulation of insulin-induced gene (Insig)-1 in the liver which was observed in
rats fed oxidized fat (Koch et al., 2007b). Koch et al. (2007b) proposed that the
effect on Insig-1 is due to activation of PPAR because it was recently shown
that synthetic PPAR activators also cause an up-regulation of Insig-1 in the
liver (KÈnig et al., 2007). Insig are membrane proteins that reside in the
endoplasmic reticulum and play a central role in the regulation of SREBP
activation, because they prevent the translocation of SREBP from the
endoplasmic reticulum to the Golgi, where proteolytic activation of SREBP
and subsequent release of transcriptionally active forms of SREBP occur (Yang
et al., 2002; Yabe et al., 2002). As a result, the synthesis of cholesterol declines
in response to PPAR activation. Therefore, up-regulation of Insig by oxidized
fat inhibits proteolytic activation of SREBP-2 in the Golgi, thereby lowering
hepatic cholesterol synthesis and liver and plasma cholesterol concentrations.
However, whether the stimulatory effect of oxidized fat on Insig-1 expression is
indeed mediated by PPAR is uncertain, because lowering of mature SREBP-2
concentration and inhibition of cholesterol synthesis was also reported for
PPAR activators (Klopotek et al., 2006), and hydroxy and hydroperoxy fatty
acids from oxidized fats are able to activate PPAR (Nagy et al., 1998; Krey et
al., 1997). Since the oxidized fat in the study from Koch et al. (2007b) was
prepared by heating the oil for a long period (25 days) at a moderate temperature
(60 ëC), which typically leads to the formation of hydroxy and hydroperoxy fatty
acids, it is not unlikely that the stimulatory effect of oxidized fat on Insig-1
expression is indeed mediated by activation of PPAR.