Abstract
Up-regulation of peroxisome proliferator-activating receptor-α (PPARα) and increasing fatty acid oxidation are important for reducing pre-weaning mortality of pigs. We examined the time-dependent regulatory effects of PPARα activation via oral postnatal clofibrate administration (75 mg/(kg-BW·d) for up to 7 days) on mitochondrial and peroxisomal fatty acid oxidation in pigs, a species with limited hepatic fatty acid oxidative capacity due to low ketogenesis. Hepatic oxidation was increased by 44-147% (depending on fatty acid chain-length) and was attained after only 4 days of clofibrate treatment. Acyl-CoA oxidase (ACO) and carnitine palmitoyltransferase I (CPTI) activities accelerated in parallel. The increase in CPTI activity was accompanied by a rapid reduction in the sensitivity of CPTI to malonyl-CoA inhibition. The mRNA abundance of CPTI and ACO, as well as peroxisomal keto-acyl-CoA thiolase (KetoACoA) and mitochondrial malonyl-CoA decarboxylase (MCD), also were augmented greatly. However, the increase in ACO activity and MCD expression were different from CPTI, and significant interactions were observed between postnatal age and clofibrate administration. Furthermore, the expression of acetyl-CoA carboxylase β (ACCβ) decreased with postnatal age and clofibrate had no effect on its expression. Collectively these results demonstrate that the expression of PPARα target genes and the increase in fatty acid oxidation induced by clofibrate are time- and age-dependent in the liver of neonatal pigs. Although the induction patterns of CPTI, MCD, ACO, KetoACoA, and ACCβ are different during the early postnatal period, 4 days of exposure to clofibrate were sufficient to robustly accelerate fatty acid oxidation.
Highlights
Milk fat is a critical macronutrient for the fast growth and development of all mammalian neonates after birth
These results demonstrate that the expression of peroxisome proliferator-activating receptor-α (PPARα) target genes and the increase in fatty acid oxidation induced by clofibrate are time- and age-dependent in the liver of neonatal pigs
Piglet mortality remains high through the first week of life [28], and perinatal programming of energy metabolism is very dynamic, continuing during the early postnatal period
Summary
Milk fat is a critical macronutrient for the fast growth and development of all mammalian neonates after birth. Available evidence suggests that the neonatal piglet has a limited capacity to catabolize dietary fatty acids, and a one-day-old pig oxidizes fatty acids at only 32% of the rate of a 24-day-old pig [2]. The postnatal regulation of fatty acid oxidation has been studied in newborn piglets to understand milk fat utilization [6,7,8,9]. Results indicate that the limited capacity of piglets to utilize fatty acids is in part associated with mutated gene transcription and translation [6,7,8,9], as well as the unique protein structures of key enzymes in the fatty acid oxidative pathway [10]
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