Pharmacogenetic Model of Retinoic Acid-Induced Dyslipidemia and Insulin Resistance

Abstract

Aims: Therapeutic administration of retinoids is often accompanied with undesirable side effects, including an increase in lipid levels in up to 45% of treated patients. We tested the hypothesis of whether spontaneously hypertensive rat (SHR) and congenic SHR.PD-(D8Rat42-D8Arb23)/Cub (SHR-Lx) strains, differing only in a 14-gene region of chromosome 8 and previously shown to display differential sensitivity to the teratogenic effects of retinoic acid, could serve as a pharmacogenetic model set of the metabolic side effects of retinoid therapy. Materials & methods: Male, 15-week old rats (n = 12/strain) of SHR and SHR-Lx strains were fed a high-sucrose diet for 2 weeks and subsequently treated either with all-trans retinoic acid (15 mg/kg) or only with a vehicle for 16 days (n = 6/strain/treatment), while still on the high-sucrose diet. We assessed the morphometric and metabolic profiles of all groups, including glucose tolerance tests, levels of insulin, adiponectin, free fatty acids, concentrations of triglycerides and cholesterol in 20 lipoprotein fractions under conditions of both high-sucrose diet and high-sucrose diet plus all-trans retinoic acid administration. Results & conclusion: SHR-Lx displayed substantially greater sensitivity to a number of all-trans retinoic acid-induced metabolic dysregulations compared with SHR, resulting in impairment of glucose tolerance, increased visceral adiposity, and substantially greater increase of circulating triglyceride concentrations, accompanied by a shift towards their less favorable distribution into the lipoprotein fractions. These observations closely mimic the common side effects of retinoid therapy in humans, rendering SHR-Lx an experimental pharmacogenetic model of atRA-induced dyslipidemia.

KEYWORDS::

• cholesterol
• comparative genomics
• congenic strain
• insulin resistance
• metabolic syndrome
• retinoid
• SHR
• triglyceride

Supplementary data

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Financial & competing interests disclosure

This work was supported by the following grants: Research Project MSM 0021620807, NR 9387–3 from the Internal Grant Agency of the Ministry of Health of Czech Republic, Czech Science Foundation, grant number 304/06/0116 to Drahomíra Křenová. Ludmila Kazdová is partly supported by the institutional financial support of the Institute for Clinical and Experimental Medicine (MZO 00023001). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was supported by the following grants: Research Project MSM 0021620807, NR 9387–3 from the Internal Grant Agency of the Ministry of Health of Czech Republic, Czech Science Foundation, grant number 304/06/0116 to Drahomíra Křenová. Ludmila Kazdová is partly supported by the institutional financial support of the Institute for Clinical and Experimental Medicine (MZO 00023001). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.