Transplacental induction of fatty acid oxidation in term fetal pigs by the peroxisome proliferator-activated receptor alpha agonist clofibrate

Abstract

BackgroundTo induce peroxisomal proliferator-activated receptor α (PPARα) expression and increase milk fat utilization in pigs at birth, the effect of maternal feeding of the PPARα agonist, clofibrate (2-(4-chlorophenoxy)-2-methyl-propanoic acid, ethyl ester), on fatty acid oxidation was examined at full-term delivery (0 h) and 24 h after delivery in this study. Each group of pigs (n = 10) was delivered from pregnant sows fed a commercial diet with or without 0.8% clofibrate for the last 7 d of gestation. Blood samples were collected from the utero-ovarian artery of the sows and the umbilical cords of the pigs as they were removed from the sows by C-section on day 113 of gestation.ResultsHPLC analysis identified that clofibric acid was present in the plasma of the clofibrate-fed sow (~4.2 μg/mL) and its offspring (~1.5 μg/mL). Furthermore, the maternal-fed clofibrate had no impact on the liver weight of the pigs at 0 h and 24 h, but hepatic fatty acid oxidation examined in fresh homogenates showed that clofibrate increased (P < 0.01) 14C-accumulation in CO2 and acid soluble products 2.9-fold from [1-14C]-oleic acid and 1.6-fold from [1-14C]-lignoceric acid respectively. Correspondingly, clofibrate increased fetal hepatic carnitine palmitoyltransferase (CPT) and acyl-CoA oxidase (ACO) activities by 36% and 42% over controls (P < 0.036). The mRNA abundance of CPT I was 20-fold higher in pigs exposed to clofibrate (P < 0.0001) but no differences were detected for ACO and PPARα mRNA between the two groups.ConclusionThese data demonstrate that dietary clofibrate is absorbed by the sow, crosses the placental membrane, and enters fetal circulation to induce hepatic fatty acid oxidation by increasing the CPT and ACO activities of the newborn.

Pharmacologic activation of peroxisome proliferator-activating receptor-α accelerates hepatic fatty acid oxidation in neonatal pigs

“…Consistent with our previous studies [ 26 , 27 , 30 ], Clo administration significantly increased hepatic fatty acid oxidative capacity. The increase was driven by increased CPTI and ACO activities induced by the administration of Clo.…”

“…We showed that clofibrate effectively stimulated in vitro fatty acid oxidation in tissue homogenates and hepatocytes isolated from newborn pigs [ 25 ] and in vivo oxidation in neonatal pigs following orogastric gavage [ 26 ]. Most recently we showed that fatty acid oxidation was increased in newborn pigs after their dams were fed clofibrate during the last week of gestation [ 27 ]. The results from our studies demonstrated that PPARα activation indeed played an important role in fatty acid oxidative metabolism in pigs during the fetus-to-newborn transition and suckling periods.…”

Activation of PPARα by Oral Clofibrate Increases Renal Fatty Acid Oxidation in Developing Pigs

“…In addition, we did not find any difference in renal PPARα and ACO mRNA enrichments between control and clofibrate-treated piglets. The low response of PPARα and ACO mRNA to clofibrate induction was observed in the livers of newborn, 24-hour-old, and 4-day-old fasted neonatal piglets [ 21 , 23 , 24 ]. Besides, the ACO activity measured in kidneys of 14-day-old control pigs was not different from pigs treated with clofibrate [ 21 ].…”

“…The incubation was stopped after 30 min by the addition of 0.5 mL of 35% HClO 4 . The 14 C accumulation in CO 2 and acid-soluble products (ASP) were collected, processed, and analyzed by liquid scintillation spectrometry (Beckman LS 6000IC, Fullerton, CA, USA) according to the procedures by Lin et al [ 24 ].…”

“…The fatty acyl-CoA oxidase (ACO) activity was measured by using a fluorometric procedure with scopoletin, a fluorescing compound as described previously [ 24 ]. The reduction of the ACO produced H 2 O 2 was coupled to the oxidation of scopoletin to its non-fluorescing product.…”