2-Chlorofatty Acid -Oxidation
REFERENCES
tectable intermediates (e.g. 12, 10, and 8 carbon ␣-ClDCA)
may be due to either subsequent steps of -oxidation being
rapid or the intermediates being present as CoA or carnitine
metabolites.
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The complexity of the system is further suggested by the
variations in relative cellular concentrations of the different
␣-ClDCA. 2-ClHDDA is the first product of -oxidation that
enters the peroxisomal -oxidation cycle as the di-carboxyl-
CoA (47). Its concentration peaked at 4 h followed by a drop
in its cellular concentration by 8 h. These temporal observa-
tions were best illustrated with 50 M 2-ClHA treatments.
Using primary rat hepatocytes, it has been shown that 2-hexa-
decane-dioic acid, the product of -oxidation, causes an in-
duction of peroxisomal -oxidation (48). While the time
period of incubation was 3 days in the study, earlier
time points were not measured. Along with secretion of
2-ClHDDA in the media, a similar induction or optimal
activation of peroxisomal -oxidation could explain the
drop in 2-ClHDDA levels. It should also be noted that, with
50 M 2-ClHA incubation, 2-ClTDDA and 2-ClAdA levels
peak between 4 and 8 h. Dicarboxylic acids are also
thought to contribute to the mitochondrial dysfunction
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Under basal conditions, -oxidation is the predominant
pathway of fatty acid metabolism, and -oxidation is thought
to contribute only up to 10% (25). It has been appreciated that
in diseases associated with high risk of heart disease, such as
obesity and diabetes, -oxidation plays an increased meta-
bolic role (26–29). It is likely that 2-ClHA, by analogy with
2-bromopalmitic acid (24), might not undergo -oxidation.
Thus, -oxidation may serve as the primary metabolic path-
way for ␣-ClFA. The utilization of this pathway for ␣-ClFA
catabolism would be analogous to the use of this pathway in
children with in-born errors of -oxidation of fatty acids,
which leads to elevated urinary AdA levels (45, 51). Thus, ei-
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demonstration, herein, that systemic circulating 2-Cl-[d2-
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The identification of these additional metabolites (e.g.
␣-ClDCA) originating from the oxidation of plasmalogens by
HOCl extends the chlorinated lipidome and metabolites of
this lipidome. Additionally, metabolism of 2-ClHA likely has
an important role in regulating levels of biologically active
chlorinated lipids. Alternatively, by analogy to nonhaloge-
nated DCA species, these ␣-ClDCA species may have inher-
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41268 JOURNAL OF BIOLOGICAL CHEMISTRY
VOLUME 285•NUMBER 53•DECEMBER 31, 2010