Additional file 1: Table S1. of Associations between fatty acid oxidation, hepatic mitochondrial function, and plasma acylcarnitine levels in mice

Overview of results. (DOCX 101 kb

Hepatic energy parameters in male Wistar rats after three weeks of treatment.

<p>(A) Energy charge (ATP + 0.5 ADP)/(AMP + ADP + ATP). (B) Ratio of AMP and ATP. Values are shown as mean ± SD (n = 6–8). One-Way ANOVA with p<0.05 was followed by Fisher LSD to determine significant difference between all three groups: Different letters above bars indicate significant difference between group mean values, p<0.05; same letters above bars indicate no significant difference between group mean values p>0.05. C–Control, M–Mildronate (550 mg/kg body weight), MT–combination of Mildronate (550 mg/kg body weight) and 1-triple TTA (100 mg/ kg body weight).</p

Hepatic gene expression in Wistar male rats after three weeks of treatment.

<p>Hepatic gene expression in Wistar male rats after three weeks of treatment.</p

Hepatic β-oxidation and enzyme activities involved in lipid catabolism in male Wistar rats after three weeks of treatment.

<p>(A) Total β-oxidation of palmitoyl-CoA in liver; (B) Total β-oxidation of palmitoyl-CoA with addition of malonyl-CoA in liver; (C) Enzyme activity of acyl-CoA synthetase; (D) Enzyme activity of carnitine palmitoyltransferase (CPT) 2; (E) Enzyme activity of 3-ketothiolase; (F) Enzyme activity of malonyl-CoA decarboxylase (MCD); (G) Enzyme activity of acyl-CoA oxidase (ACOX); (H) Enzyme activity of citrate synthase. Values are shown as means ± SD (n = 6–8). One-Way ANOVA with p<0.05 was followed by Fisher LSD to determine significant difference between all three groups: Different letters above bars indicate significant difference between group mean values, p<0.05; same letters above bars indicate no significant difference between group mean values p>0.05. C–Control, M–Mildronate (550 mg/kg body weight), MT–combination of Mildronate (550 mg/kg body weight) and 1-triple TTA (100 mg/ kg body weight).</p

Hepatic enzyme activities involved in lipid anabolism in male Wistar rats after three weeks of treatment.

<p>(A) Enzyme activity of acetyl-CoA carboxylase (ACC). (B) Enzyme activity of fatty acid synthase (FAS). (C) Enzyme activity of citrate-ATP lyase. (D) Enzyme activity of glycerol-3-phosphate transferase (GPAT). Values are shown as mean± SD (n = 6–8). One-Way ANOVA with p<0.05 was followed by Fisher LSD to determine significant difference between all three groups: Different letters above bars indicate significant difference between group mean values, p<0.05; same letters above bars indicate no significant difference between group mean values p>0.05. C–Control, M–Mildronate (550 mg/kg body weight), MT–combination of Mildronate (550 mg/kg body weight) and 1-triple TTA (100 mg/ kg body weight).</p

Plasma and liver lipids in male Wistar rats after three weeks of treatment.

<p>Plasma and liver lipids in male Wistar rats after three weeks of treatment.</p

Plasma levels of carnitine derivatives and carnitine precursors in male Wistar rats after three weeks of treatment.

<p><b>A.</b> Plasma L-carnitine; <b>B.</b> Plasma acetylcarnitine; <b>C.</b> Plasma γ-butyrobetaine; <b>D.</b> Plasma trimethyllysine; <b>E.</b> Protein expression of carnitine translocase (CACT). Values are shown as mean ± SD (n = 6–8). One-Way ANOVA with p<0.05 was followed by Fisher LSD to determine significant difference between all three groups. Different letters above bars indicate significant difference between group mean values, p<0.05; same letters above bars indicate no significant difference between group mean values p>0.05. C–Control, M–Mildronate (550 mg/kg body weight), MT–combination of Mildronate (550 mg/kg body weight) and 1-triple TTA (100 mg/ kg body weight).</p

Asymmetric dimethylarginine and trimethyllysine before and after supplementation with folic acid/vitamin B₁₂.

<p>The graph shows empirical cumulative distribution frequencies for asymmetric dimethylarginine on the left and trimethyllysine on the right. Patients receiving folic acid/B₁₂ are displayed on the top, while patients receiving placebo or B₆ on the bottom. Time of measurement is shown as baseline (solid line) and follow-up (dashed line) after a median of 10.5 month.</p

Fish Oil and the Pan-PPAR Agonist Tetradecylthioacetic Acid Affect the Amino Acid and Carnitine Metabolism in Rats

<div><p>Peroxisome proliferator-activated receptors (PPARs) are important in the regulation of lipid and glucose metabolism. Recent studies have shown that PPARα-activation by WY 14,643 regulates the metabolism of amino acids. We investigated the effect of PPAR activation on plasma amino acid levels using two PPARα activators with different ligand binding properties, tetradecylthioacetic acid (TTA) and fish oil, where the pan-PPAR agonist TTA is a more potent ligand than omega-3 polyunsaturated fatty acids. In addition, plasma L-carnitine esters were investigated to reflect cellular fatty acid catabolism. Male Wistar rats (<i>Rattus norvegicus</i>) were fed a high-fat (25% w/w) diet including TTA (0.375%, w/w), fish oil (10%, w/w) or a combination of both. The rats were fed for 50 weeks, and although TTA and fish oil had hypotriglyceridemic effects in these animals, only TTA lowered the body weight gain compared to high fat control animals. Distinct dietary effects of fish oil and TTA were observed on plasma amino acid composition. Administration of TTA led to increased plasma levels of the majority of amino acids, except arginine and lysine, which were reduced. Fish oil however, increased plasma levels of only a few amino acids, and the combination showed an intermediate or TTA-dominated effect. On the other hand, TTA and fish oil additively reduced plasma levels of the L-carnitine precursor γ-butyrobetaine, as well as the carnitine esters acetylcarnitine, propionylcarnitine, valeryl/isovalerylcarnitine, and octanoylcarnitine. These data suggest that while both fish oil and TTA affect lipid metabolism, strong PPARα activation is required to obtain effects on amino acid plasma levels. TTA and fish oil may influence amino acid metabolism through different metabolic mechanisms.</p></div

Diameter stenosis at follow-up according to plasma concentrations of asymmetric dimethylarginine and trimethyllysine^a.

<p>DS, Diameter Stenosis; ADMA, asymmetric dimethylarginine; TML, trimethyllysine.</p>a<p>Non-parametric linear quantile mixed-effects models of diameter stenosis at follow-up using Laplace distribution.</p>b<p>Effect estimate given as regression coefficient (95% confidence interval) and p-value for change in percentage point diameter stenosis.</p>c<p>The fixed effect in this model is ADMA and DS measured at baseline while the random effect is the clustering of arterial segments within a single patient. Estimates are presented as median (95% confidence interval). Standard error is estimated using bootstrapping.</p>d<p>The fixed effect in this model is TML and DS measured at baseline while the random effect is the clustering of arterial segments within a single patient. Estimates are presented as median (95% confidence interval). Standard error is estimated using bootstrapping.</p>e<p>The fixed effect in this model is DS measured at baseline, follow-up time in days, presence of diabetes, randomization (folic acid/B₁₂ vs no folic acid/B₁₂) status at baseline, plasma TML at baseline, smoking status, age, gender, plasma ADMA at baseline, systolic blood pressure, body mass index, kidney function, apolioprotein B100 and C-reactive protein while the random effect is the clustering of arterial segments within a single patient. Standard error is estimated using bootstrapping.</p