Deficiency or activation of peroxisome proliferator-activated receptor α reduces the tissue concentrations of endogenously synthesized docosahexaenoic acid in C57BL/6J mice

BACKGROUND/OBJECTIVES: Docosahexaenoic acid (DHA), an n-3 long chain polyunsaturated fatty acid (LCPUFA), is acquired by dietary intake or the in vivo conversion of α-linolenic acid. Many enzymes participating in LCPUFA synthesis are regulated by peroxisome proliferator-activated receptor alpha (PPARα). Therefore, it was hypothesized that the tissue accretion of endogenously synthesized DHA could be modified by PPARα. MATERIALS/METHODS: The tissue DHA concentrations and mRNA levels of genes participating in DHA biosynthesis were compared among PPARα homozygous (KO), heterozygous (HZ), and wild type (WT) mice (Exp I), and between WT mice treated with clofibrate (PPARα agonist) or those not treated (Exp II). In ExpII, the expression levels of the proteins associated with DHA function in the brain cortex and retina were also measured. An n3-PUFA depleted/replenished regimen was applied to mitigate the confounding effects of maternal DHA. RESULTS: PPARα ablation reduced the hepatic Acox, Fads1, and Fads2 mRNA levels, as well as the DHA concentration in the liver, but not in the brain cortex. In contrast, PPARα activation increased hepatic Acox, Fads1, Fads2 and Elovl5 mRNA levels, but reduced the DHA concentrations in the liver, retina, and phospholipid of brain cortex, and decreased mRNA and protein levels of the brain-derived neurotrophic factor in brain cortex. CONCLUSIONS: LCPUFA enzyme expression was altered by PPARα. Either PPARα deficiency or activation-decreased tissue DHA concentration is a stimulus for further studies to determine the functional significance.

Prophylactic Effect of Clofibrate on Hyperbilirubinemia in Very Low Birth Weight Twins.

Aims: To determine the prophylactic effects of clofibrate on hyperbilirubinemia in very low birth weight twins. Study Design: A randomized double blind clinical trial Place and Duration of Study: Department of Neonatal Research Center, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran, between Oct 2010- Sep 2011. Methodology: Forty neonates with very low birth weight (20 pairs of twins) having same blood group and sex were elected. Infants with congenital anomalies, metabolic diseases, hemolytic disease, and infections were excluded. Case group received a single dose of clofibrate 100 mg/kg and control group received sterile water. Both clofibrate and sterile water were administrated through orogastric tube and were the same volume. Serum bilirubin levels were measured before administration, 24, 48, 72 and 96 hours after the administration. Data was analyzed using repeated measure ANOVA. Results: Total serum bilirubin after clofibrate administration was lower than control group (F= 6.48, P=0.02); however, the duration of phototherapy and hospitalization were not significantly different between the two groups (P=0.39 and 0.91 respectively). No side effects of drug were observed based on the physical exam and liver function tests. Conclusion: These findings suggest that clofibrate maintained total serum bilirubin lower in very low birth weight neonates but without effect on duration of phototherapy and hospitalization.

Clofibrate for Unconjugated Hyperbilirubinemia in Neonates: A Systematic Review.

Objective: To evaluate the effect of clofibrate for unconjugated hyperbilirubinemia in neonates. Methods: A systematic review with meta-analysis of randomized controlled trials or quasi-randomized controlled trials was conducted to evaluate the clofibrate treatment in neonates with unconjugated hyperbilirubinemia. We followed the guidelines from the Cochrane review group and the PRISMA statement. Results: Of 148 studies identified, a total of 13 studies on 867 infants were included. A single oral administration of clofibrate was associated with decreased need of phototherapy (RR:.38, 95% CI: 0.21 to 0.68), shortened duration of phototherapy (mean duration: 23.88 h, 95% CI: 33.03 to -14.72 h) and reduced peak total serum bilirubin (mean duration: -1.62 mg/dL, 95% CI: 2.13 to -1.11 mg/dL). These effects were especially obvious in term infants and infants without hemolytic diseases. Data regarding mortality or kernicterus were not available from included studies. Conclusions: Clofibrate may have short-term benefits for the infants with hyperbilirubinaemia, especially for population of term infants and infants without hemolytic diseases. Large RCTs with long-term followup are required to verify the safety of clofibrate and assess its long-term effects.

The effect of clofibrate with phototherapy in late pre-term newborns with non-hemolytic jaundice.

Background : Despite an understanding of the enzymatic pathways leading to bilirubin production and degradation, very few pharmacologic interventions are utilized and the mainstay of treatment remains phototherapy. Aims : To evaluate the efficacy of clofibrate in reducing total serum bilirubin levels in late pre-term neonates with non-hemolytic jaundice. Design and Setting : Double-blind, placebo-controlled, randomized trial; tertiary level neonatal unit. Materials and Methods : A randomized controlled study was carried out in the neonatal ward of Children's Hospital, Tabriz, Iran, over a 1-year period. Sixty-eight healthy late pre-term infants readmitted with non-hemolytic hyperbilirubinemia were randomized to receive phototherapy and clofibrate (n= 35) or phototherapy and placebo (n= 33). Statistical Analysis Used : Chi-square test and independent sample 't' test. Results : There were no significant differences in the weight, gender, modes of delivery and age of neonates between the two groups. Similarly the mean total serum bilirubin (TSB) level at the time of admission was not significantly different between the two groups [mean± SD: 19.72 ± 1.79 (95% confidence interval: 19.12-20.54 mg/dL) vs. 20.05 ± 2.82 (95% confidence interval, 19.54-22.04 mg/dL), P= 0.57]. The mean TSB 48 hours after phototherapy [mean± SD: 8.06± 1.34 (95% confidence interval: 7.94-10.18 mg/dL) vs.10.94 ± 2.87 (95% confidence interval: 9.92-12.16 mg/dL), P= 0.02] and the mean duration of phototherapy [mean± SD: 64.32 ± 12.48 (95% confidence interval: 60-81.6 hours) vs. 87.84 ± 29.76 (95% confidence interval: 79.2-108 hours), P< 0.001] were significantly lower in the clofibrate-treated group. Conclusions : Clofibrate is an effective adjunctive drug in neonatal hyperbilirubinemia, which results in decreased TSB level and reduced duration of phototherapy in late pre-term newborns.

A STUDY OF STRUCTURE-EFFECT RELATIONSHIP OF CLOFIBRATE AND ITS HOMOLOGUE / 中国药理学通报

Effects of decreasing serum cholesterol & structure-effect relation ships of clofibrate & its homologue were studied in this paper . The model of high lipid animal was made by ip yolk emulsion. Effects of 3 drugs for serum cholesterol were observed . These results showed that clofibrate (200mg/kg) & ethyl-p-acetaminophenoxy-ac etate (200,100mg/kg) both lowered serum cholesterol levels (P