Pharmacogenomic analysis of retinoic-acid induced dyslipidemia in congenic rat model

Lipids in Health and Disease

Research

Lucie Šedová¹  Drahomíra Křenová¹  Michaela Krupková¹  František Liška¹  Vladimír Křen¹  Ondřej Šeda² 

[1] Institute of Biology and Medical Genetics, the First Faculty of Medicine, Charles University and the General Teaching Hospital, Albertov 4, 12800, Prague, Czech Republic;Institute of Biology and Medical Genetics, the First Faculty of Medicine, Charles University and the General Teaching Hospital, Albertov 4, 12800, Prague, Czech Republic;Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic, Vídeňská 1083, 142 20, Prague 4, Czech Republic;

关键词: Pharmacogenomics;    Metabolic syndrome;    Animal model;    Muscle transcriptome;    All-trans retinoic acid;    Zbtb16;   

DOI  :  10.1186/1476-511X-13-172

 received in 2014-08-03, accepted in 2014-10-29,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundAll-trans retinoic acid (ATRA, tretinoin) is a vitamin A derivative commonly used in the treatment of diverse conditions ranging from cancer to acne. In a fraction of predisposed individuals, the administration of ATRA is accompanied by variety of adverse metabolic effects, particularly by the induction of hyperlipidemia. We have previously derived a minimal congenic SHR.PD-(D8Rat42-D8Arb23)/Cub (SHR-Lx) strain sensitive to ATRA-induced increase of triacylglycerols and cholesterol under condition of high-sucrose diet. SHR-Lx differs only by 7 genes of polydactylous rat (PD/Cub) origin from its spontaneously hypertensive rat (SHR) progenitor strain.MethodsAdult male rats of SHR and SHR-Lx strains were fed standard diet (STD) and experimental groups were subsequently treated with ATRA (15 mg/kg) via oral gavage for 16 days, while still on STD. We contrasted the metabolic profiles (including free fatty acids, triacylglycerols (TG) and cholesterol (C) in 20 lipoprotein fractions) between SHR and SHR-Lx under conditions of standard diet and standard diet + ATRA. 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.ResultsIn response to ATRA, 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).ConclusionsAccording to our modeling of metabolic and signalization pathways using differentially expressed genes we have identified a network with major nodes (including Sirt3, Il1b, Cpt1b and Pparg) likely to underlie the observed strain specific response to ATRA.

【 授权许可】

Unknown   
© Krupková et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.