Our previous work has found that pregnant rats subjected to protein restriction throughout gestation and lactation results in offspring that are characterized by lower birth weight with sustainment into adulthood, hyperphagia, an increased efficiency in converting energy to growth as suggested by increased insulin sensitivity, reduced epididymal fat levels, and decreased triglyceride (Tg) levels in the liver and plasma. Several of these characteristics, especially the decrease in plasma Tg levels, are similar to the effects of the fibrate drug class. Our overall objective was to determine the role of fatty acid transporters in mediating the effects of perinatal protein restriction and fibrates in lowering of plasma and liver Tg levels. We hypothesized that the lower plasma and liver Tg levels would be associated with altered expression of fatty acid transporters within lipid utilizing tissues in these two groups of animals. In the first phase, rats that were protein restricted during gestation and lactation and then weaned onto regular laboratory chow were sacrificed on day 65. In the second phase, adult rats were chronically treated with fenofibrate, an agonist of the nuclear peroxisome proliferatoractivated receptor alpha (PPAR α), for 7 days and then sacrificed. Plasma, liver, gastrocnemius muscle, heart, and epididymal fat pad were collected from animals in both phases. The mRNA expression of fatty acid transporters were measured using reverse transcription quantitative polymerase chain reaction (RT-qPCR). We found no differences in the expression of a variety of fatty acid transporters between low protein III (LP) and control offspring either in the liver or in other major fatty acid utilizing tissues such as gastrocnemius muscle, heart, and epididymal adipose tissue. These results suggest that fatty acid transporters in these tissues have a minimal role in regulating plasma and liver levels of Tg in LP offspring. In contrast, fenofibrate decreases plasma Tg levels and that was associated with altered expression of several fatty acid transporters in the liver, heart, muscle and epididymal fat. We observed an unexpected and substantial increase in the liver expression of the heart fatty acid binding protein 3 (Fabp3), a previously proposed biomarker for muscle toxicity produced by PPARα agonists. This novel finding complicates use of Fabp3 as a biomarker for preclinical PPARα muscle toxicity.
|Advisor:||D'mello, Anil P.|
|School:||University of the Sciences in Philadelphia|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 78/02(E), Dissertation Abstracts International|
|Keywords:||Acid, Fatty, Fenofibrate, Homeostasis, Lipid, Offspring, Perinatally, Restricted, Transporters, Treated|
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