Abstract
BackgroundNon-alcoholic fatty liver disease is often associated with obesity, insulin resistance, dyslipidemia, and the metabolic syndrome in addition to mitochondrial dysfunction and nicotinamide adenine dinucleotide (NAD+) deficiency. The aim of this study was to investigate how inhibition of mitochondrial fatty acid oxidation using the compound tetradecylthiopropionic acid (TTP) would affect hepatic triacylglycerol level and plasma levels of kynurenine (Kyn) metabolites and nicotinamide.Methods12 C57BL/6 mice were fed a control diet, or an intervention diet supplemented with 0.9% (w/w) tetradecylthiopropionic acid for 14 days. Blood and liver samples were collected, enzyme activities and gene expression were analyzed in liver, in addition to fatty acid composition. Metabolites in the tryptophan/kynurenine pathway and total antioxidant status were measured in plasma.ResultsDietary treatment with tetradecylthiopropionic acid for 2 weeks induced fatty liver accompanied by decreased mitochondrial fatty acid oxidation. The liver content of the oxidized form of NAD+ was increased, as well as the ratio of NAD+/NADH, and these changes were associated by increased hepatic mRNA levels of NAD synthetase and nicotinamide mononucleotide adenyltransferase-3. The downstream metabolites of kynurenine were reduced in plasma whereas the plasma nicotinamide content was increased. Some effects on inflammation and oxidative stress was observed in the liver, while the plasma antioxidant capacity was increased. This was accompanied by a reduced plasma ratio of kynurenine/tryptophan. In addition, a significant decrease in the inflammation-related arachidonic fatty acid in liver was observed.ConclusionFatty liver induced by short-time treatment with tetradecylthiopropionic acid decreased the levels of kynurenine metabolites but increased the plasma levels of NAD+ and nicotinamide. These changes are most likely not associated with increased inflammation and oxidative stress. Most probably the increase of NAD+ and nicotinamide are generated through the Preiss Handler pathway and/or salvage pathway and not through the de novo pathway.The take home message is that non-alcoholic fatty liver disease is associated with the metabolic syndrome in addition to mitochondrial dysfunction and nicotinamide adenine dinucleotide (NAD+) deficiency. Inducing fatty liver in mice by inhibition of fatty acid oxidation resulted in a concomitant change in kynurenine metabolites increasing the plasma levels of nicotinamides and the hepatic NAD+/NADH ratio, probably without affecting the de novo pathway of kynurenines.
Highlights
Non-alcoholic fatty liver disease is often associated with obesity, insulin resistance, dyslipidemia, and the metabolic syndrome in addition to mitochondrial dysfunction and nicotinamide adenine dinucleotide (NAD+) deficiency
The take home message is that non-alcoholic fatty liver disease is associated with the metabolic syndrome in addition to mitochondrial dysfunction and nicotinamide adenine dinucleotide (NAD+) deficiency
tetradecylthiopropionic acid (TTP) increases triacylglycerol (TAG) level and reduces mitochondrial fatty acid oxidation in liver without association with oxidative stress and inflammation The feed intake, feed efficiency, body weight, as well as liver weight were not affected by TTP administration in mice, but oil-red-O staining indicated that hepatic steatosis was induced (Fig. 2a)
Summary
Non-alcoholic fatty liver disease is often associated with obesity, insulin resistance, dyslipidemia, and the metabolic syndrome in addition to mitochondrial dysfunction and nicotinamide adenine dinucleotide (NAD+) deficiency. The aim of this study was to investigate how inhibition of mitochondrial fatty acid oxidation using the compound tetradecylthiopropionic acid (TTP) would affect hepatic triacylglycerol level and plasma levels of kynurenine (Kyn) metabolites and nicotinamide. Mitochondria are the major source of reactive oxygen species and both the oxidized form of nicotinamide (NAD+) and the reduced form NADH are important cofactors for the redox state. De novo biosynthesis of NAD takes place through tryptophan (Trp) catabolism by the kynurenine (Kyn) pathway (Fig. 1). Mitochondrial fatty acid oxidation needs NAD+ as a cofactor, and interestingly, the enzymes responsible for the generation of Kyn metabolites are present in both mitochondria and/or cytosol [1, 2]. Alterations in the Trp-metabolism, such as changes in enzyme activity or gene expression as well as substrate availability may influence mitochondrial function or vice versa. The plasma Kyn/Trp ratio (KTR), which increases during inflammation [4], is influenced by the activities of both
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