Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-511X-13-172) contains supplementary material, which is available to authorized users.
Highlights
All-trans retinoic acid (ATRA, tretinoin) is a vitamin A derivative commonly used in the treatment of diverse conditions ranging from cancer to acne
We have investigated whether the sensitivity of spontaneously hypertensive rat (SHR)-Lx to ATRA-induced dyslipidemia is present under standard diet condition
We explored whether the pharmacogenetic interaction of RA and the differential segment is reflected in the transcriptome of skeletal muscle, the tissue shown to be metabolically challenged in the SHR-Lx [12]
Summary
All-trans retinoic acid (ATRA, tretinoin) is a vitamin A derivative commonly used in the treatment of diverse conditions ranging from cancer to acne. All-trans-retinoic acid (ATRA, tretinoin) is a vitamin A derivative that serves as a prominent hub of many signaling and metabolic pathways involved in range of processes from development to energy homeostasis [1]. Both excess and shortage of ATRA were shown to have pathophysiological consequences and rather tight maintenance of ATRA levels is necessary both in development and adult life in order to prevent disease manifestation [2]. We explored whether the pharmacogenetic interaction of RA and the differential segment is reflected in the transcriptome of skeletal muscle, the tissue shown to be metabolically challenged in the SHR-Lx [12]
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