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


METHODS
Adult 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.


RESULTS
In 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).


CONCLUSIONS
According 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.
Michaela
M
Krupková
František
F
Liška
Lucie
L
Sedová
Drahomíra
D
Křenová
Vladimír
V
Křen
Institute of Biology and Medical Genetics, the First Faculty of Medicine, Charles University and the General Teaching Hospital, Albertov 4, 12800 Prague, Czech Republic. oseda@lf1.cuni.cz.
Ondřej
O
Seda
D000818:Animals; D050171:Dyslipidemias / Q000097:blood / Q000139:chemically induced* / Q000235:genetics*; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism; D011918:Rats, Inbred SHR; D059467:Transcriptome; D014212:Tretinoin
D008055:Lipids; D014212:Tretinoin