Abstract 432: Modification of Lipid Spectrum and Skeletal Muscle Transcriptome Due to Pharmacogenetic Interaction of Retinoic Acid With Rat Chromosome 8
Background: Polydactylous rat strain PD/Cub and spontaneously hypertensive rat SHR are two established rodent models of human metabolic syndrome. In the process of positional cloning of apparently pleiotropic locus on rat chromosome 8 affecting major features of metabolic syndrome including dyslipidemia we have derived the minimal congenic SHR.PD-(D8Rat42-D8Arb23)/Cub (SHR-Lx) strain carrying only 7 genes of PD origin on SHR background.
Design: Adult male rats of SHR and SHR-Lx strains were fed standard diet (STD) and subsequently treated with retinoic acid (atRA, 15 mg/kg) via oral gavage for 16 days, while still on STD. We contrasted metabolic profiles (incl. oral glucose tolerance test, free fatty acids, triglyceride and cholesterol in 20 lipoprotein fractions) between SHR and SHR-Lx under conditions of standard diet and standard diet + RA administration. We performed transcriptomic analysis of muscle tissue (m. soleus) in all groups using Affymetrix GeneChip Rat Gene 2.0 ST Arrays followed by Ingenuity Pathway Analysis and real-time PCR validation.
Results: : In response to RA, SHR-Lx reacted with substantially greater rise in TG and C concentrations throughout the lipoprotein spectrum (two-way ANOVA strain * RA interaction significant for C content in chylomicrons(CM), VLDL and LDL as well as total, CM and HDL-TG). According to our modeling of metabolic and signalization pathways using differentially expressed genes we have identified a network with major nodes (Sirt3, Il1b, Cpt1b, Gria2, Pparg, Rdh11) likely to the observed metabolic differences.
Conclusions: We demonstrated that pharmacogenetic interaction of retinoic acid with a 7- gene region of rat chromosome 8 affects the distribution of cholesterol and triglycerides into the lipoprotein fractions along with other features of metabolic syndrome. Changed expression of network nodes Pparg, Il1b, Sirt3 and Cpt1b appears as central for observed interaction.
Author Disclosures: M. Krupkova: None. M. Janku: None. F. Liska: None. L. Sedova: None. M. Hodulova: None. D. Krenova: None. V. Kren: None. O. Seda: None.
- © 2014 by American Heart Association, Inc.