Endotoxin-mediated pathway

Endotoxin treatment of rodents leading to inflammation has been shown to lead to the production of chlorinated lipids. As previously described, Sattler and coworkers showed that endotoxin treatment led to neuroinflammation with concomitant increased levels of both MPO mRNA and 2-chlorohexadecanal in the brain (Ullen et al. 2010). Our studies have also shown that endotoxin leads to chlorinated lipid production in various systems in vivo (Brahmbhatt et al. 2010). In fact, lipopolysaccharide treatment led to elevated 2-chlorohexadecanoic acid levels in the plasma. These studies also delineated the metabolic clearance pathway for 2-chlorohexadecanoic acid, which is mediated by sequential hepatic co-oxidation, P-oxidation from the co-end, and then subsequent excretion of 2-chloroadipic acid in the urine (Figure 4.3). Furthermore, lipopolysaccharide treatment of rats led to not only the elevation of plasma 2-chlorohexadecanoic acid, but also increased excretion of 2-chloroadipic acid in the urine. 

It is too early to definitively identify the molecular mechanism(s) by which CLA, or specific isomers thereof, modulate immune reactivity and reduce disease. Peroxisomal proliferator-activated receptor-y (PPAR-y) activation has been proposed as a mechanism by which CLA exerts some of its biological effects (23). Although PPAR-y may play a role in some of the effects caused by dietary CLA, and these effects could be mediated via the downregulation of the NFkB pathway (24), there are some inconsistencies in the isomer-specific effects on the regulation of COX-2 and some of the products of the NFkB pathway. For example, Yu et al. (23) demonstrated that both the t9,cll and the tl0,cl2 isomers of CLA increase PPAR-y, and decrease TNFa however, only the c9,tll isomer decreased endotoxin-induced TNFa (12). If CLA-fed animals are more resistant to endotoxin (above) and if endotoxin downregulates PPAR-y (24), could PPAR-y regulation explain the wide array of effects attributed to dietary CLA ... 

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