Abstract
Administration of pivalate has been demonstrated to be suitable for the induction of secondary carnitine deficiency (CD) in pigs, as model objects for humans. In order to comprehensively characterize the metabolic effects of secondary CD in the liver of pigs, the present study aimed to carry out comparative analysis of the hepatic transcriptome and hepatic and plasma metabolome of a total of 12 male 5-week-old pigs administered either pivalate (group PIV, n = 6) or vehicle (group CON, n = 6) for 28 days. Pigs of group PIV had approximately 40–60% lower concentrations of free carnitine and acetylcarnitine in plasma, liver and different skeletal muscles than pigs of group CON (p < 0.05). Transcript profiling of the liver revealed 140 differentially expressed genes (DEGs) between group PIV and group CON (fold change > 1.2 or <−1.2, p-value < 0.05). Biological process terms dealing with the innate immune response were found to be enriched with the DEGs (p < 0.05). Using a targeted metabolomics approach for the simultaneous quantification of 630 metabolites, 9 liver metabolites and 18 plasma metabolites were identified to be different between group PIV and group CON (p < 0.05). Considering the limited alterations of the hepatic transcriptome and of the liver and plasma metabolome, it can be concluded that pivalate-induced secondary CD is not associated with significant hepatic metabolism changes in pigs.
Highlights
Water-soluble carnitine is essential for the normal functioning of all tissues that contain mitochondria due to its well-documented role in the import of long-chain fatty acids into the mitochondrial matrix for subsequent β-oxidation [1]
Sporadic cases of secondary carnitine deficiency (CD) are known to occur as a result of long-term (>14 days) oral administration of pivalate-conjugated antibiotics, mainly in pediatric patients [12,13,14], because the pivaloyl moiety of these antibiotics binds free carnitine, leading to the formation of pivaloylcarnitine, which is excreted via urine in quantities exceeding endogenous carnitine synthesis
Pigs of group PIV had approximately 40–60% lower concentrations of free carnitine and acetylcarnitine in the plasma and liver, and in different skeletal muscles, than pigs of group CON, as determined by LC-MS/MS
Summary
Water-soluble carnitine is essential for the normal functioning of all tissues that contain mitochondria due to its well-documented role in the import of long-chain fatty acids into the mitochondrial matrix for subsequent β-oxidation [1]. Individuals frequently affected by secondary CD are chronically ill patients suffering from cancer, chronic kidney disease, acquired immune deficiency syndrome, hepatitis C or hepatic encephalopathy [6,7,8,9]. In such patients, a decreased food intake, which is accompanied by a decreased intake of carnitine and specific micronutrients, such as iron, riboflavin and ascorbic acid, which are required as co-factors for carnitine synthesis, is one important reason for secondary CD. Sporadic cases of secondary CD are known to occur as a result of long-term (>14 days) oral administration of pivalate-conjugated antibiotics, mainly in pediatric patients [12,13,14], because the pivaloyl moiety of these antibiotics binds free carnitine, leading to the formation of pivaloylcarnitine, which is excreted via urine in quantities exceeding endogenous carnitine synthesis
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