Abstract
The fate of the acetyl-CoA units released during peroxisomal fatty acid oxidation was studied in isolated hepatocytes from normal and peroxisome-proliferated rats. Ketogenesis and hydrogen peroxide generation were employed as indicators of mitochondrial and peroxisomal fatty acid oxidation, respectively. Butyric and hexanoic acids were employed as mitochondrial substrates, 1, omega-dicarboxylic acids as predominantly peroxisomal substrates, and lauric acid as a substrate for both mitochondria and peroxisomes. Ketogenesis from dicarboxylic acids was either absent or very low in normal and peroxisome-proliferated hepatocytes, but free acetate release was detected at rates that could account for all the acetyl-CoA produced in peroxisomes by dicarboxylic and also by monocarboxylic acids. Mitochondrial fatty acid oxidation also led to free acetate generation but at low rates relative to ketogenesis. The origin of the acetate released was confirmed employing [1-14C]dodecanedioic acid. Thus, the activity of peroxisomes might contribute significantly to the free acetate generation known to occur during fatty acid oxidation in rats and possibly also in humans.
Highlights
The fate of the acetyl-coAunits released during peroxisomal fatty acid oxidation was studied in isolated hepatocytes from normal andperoxisome-proliferated rats
The enhancement of mitochondrial activity and the large induction of the peroxisomal fatty acid oxidation capacity correspond to a response pattern already established [8].In the presence of lauric acid, free acetate is generated at a rate which increases 6-fold after the bezafibrate-induced oxidation enhancement.Incontrast, ketone body generation is only doubled
Acetate is generated with dodecanedioic acid at a slightly higher rate than hydrogen peroxide.The striking lack of ketogenesis with dodecanedioic acid raised the possibility of a specific inhibition of ketone body synthesis
Summary
Oxidation of Different Substrates by Normal and Peroxisome-proliferated Hepatocytes-Lauric acid, a mitochondrial substrate and ketone body generator, is a good peroxisomal substrate [7, 14]. The enhancement of mitochondrial activity and the large induction of the peroxisomal fatty acid oxidation capacity correspond to a response pattern already established [8].In the presence of lauric acid, free acetate is generated at a rate which increases 6-fold after the bezafibrate-induced oxidation enhancement.Incontrast, ketone body generation is only doubled. Hydrogen peroxide and free acetate were generated at very similar rates This finding lends strong support to the hypothesis that in whole hepatocytes dicarboxylic acids are mainly peroxisomal substrates and that theacetyl-coA released in the process is transformed into free acetate. The cells were incubated with lauric acid, and production rates were0.42 f 0.01, 0.79 f 0.10, and 4.62 f 0.17 nmol x min" x mg protein" of hydrogen peroxide, acetate,and P-hydroxybutyrate plus acetoacetate, respectively. [14C]Acetate Generation from [l-'4C]Dodecanedioic AcidTo confirm the hypothesis that thesource of the free acetate generated during dicarboxylic acid oxidation is the acetyl-
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