Pharmacogenetic interaction between dexamethasone and Cd36-deficient segment of spontaneously hypertensive rat chromosome 4 affects triacylglycerol and cholesterol distribution into lipoprotein fractions

Abstract

Dexamethasone (DEX) is known to induce diabetes and dyslipidemia. We have compared fasting triacylglycerol and cholesterol concentrations across 20 lipoprotein fractions and glucose tolerance in control (standard diet) and DEX-treated 7-month-old males of two rat strains, Brown Norway (BN) and congenic BN.SHR-(Il6-Cd36)/Cub (BN.SHR4). These two inbred strains differ in a defined segment of chromosome 4, originally transferred from the spontaneously hypertensive rat (SHR) including the mutant Cd36 gene, a known target of DEX. Compared to BN, the standard-diet-fed BN.SHR4 showed higher cholesterol and triacylglycerol concentrations across many lipoprotein fractions, particularly in small VLDL and LDL particles. Total cholesterol was decreased by DEX by more than 21% in BN.SHR4 contrasting with the tendency to increase in BN (strain*DEX interaction p = 0.0017). Similar pattern was observed for triacylglycerol concentrations in LDL. The LDL particle size was significantly reduced by DEX in both strains. Also, while control BN and BN.SHR4 displayed comparable glycaemic profiles during oral glucose tolerance test, we observed a markedly blunted DEX induction of glucose intolerance in BN.SHR4 compared to BN. In summary, we report a pharmacogenetic interaction between limited genomic segment with mutated Cd36 gene and dexamethasone-induced glucose intolerance and triacylglycerol and cholesterol redistribution into lipoprotein fractions.

Heterozygous connexin 50 mutation affects metabolic syndrome attributes in spontaneously hypertensive rat

“…The resulting mutant coisogenic strain SHR-Gja8 m1Cub (SHR- Dca −/− hereafter, RGD ID: 2293729) shows decreased blood pressure compared to SHR [10]. This study aimed to further explore the effects of connexin50 mutation on metabolic and cytokine profile in SHR- Dca −/− and SHR- Dca +/− strains including a battery of parameters of oxidative stress in the animals challenged by dexamethasone, a dyslipidemia and insulin resistance-inducing glucocorticoid [11, 12]. …”

CD36-deficient congenic strains show improved glucose tolerance and distinct shifts in metabolic and transcriptomic profiles

“…Of those, only Cd36 was found to be differentially expressed between PD and PD.SHR4a. Further studies are needed to assess the effect of Cd36 and the whole differential segment under distinct nutritional and pharmacological challenges, especially given our previous extensive documentation of nutrigenetic and pharmacogenetic interactions of a similar genomic region in the BN.SHR4 congenic strain (Seda et al, 2003a(Seda et al, , 2008Krupkova et al, 2010). In sum, the introduction of mutated Cd36 into the genomic background of an inbred model of metabolic syndrome resulted in disconnected shifts of metabolic profile along with distinct changes in hepatic transcriptome.…”

“…One of the mechanisms responsible may lie in the fact that human islets express Cd36 in the plasma membrane as well as in the insulinsecretory granules, and Cd36 activity was deemed important for uptake of fatty acids into b-cells as well as for mediating their modulatory effects on insulin secretion (Noushmehr et al, 2005) . Altogether, it is apparent that the eventual metabolic effect of Cd36 deficiency is tightly linked to a particular setting of both genomic background (for example, PD.SHR4 vs BN.SHR4 (Seda et al, 2002(Seda et al, , 2003b; Table 5 and Supplementary Figure 3) and environmental factors, particularly diet (Febbraio et al, 1999;Hajri et al, 2002;Koonen et al, 2007;Kennedy et al, 2011) or medication (Qi et al, 2002;Seda et al, 2003a;Seda et al, 2008;Krupkova et al, 2010). Therefore, the apparently controversial issue of causal relation between level of Cd36 expression and metabolic outcome may be resolved by adoption of broader conceptual framework incorporating other (eco)genomic factors.…”

“…The lipid profile (cholesterol and triglyceride blood concentration in 20 lipoprotein fractions, glycerol level and chylomicron, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein particle sizes) was assessed by high-performance liquid chromatography (HPLC) as described previously (Krupkova et al, 2010;Usui et al, 2002). Serum free fatty acids were determined using an acyl-CoA oxidase-based colorimetric kit (Roche Diagnostics GmbH, Mannheim, Germany).…”

“…Furthermore, we have found this limited portion of genome to be crucial for several pharmacogenetic interactions involving the insulin sensitizer rosiglitazone (Seda et al, 2003a(Seda et al, , 2008 and glucocorticoid dexamethasone (Krupkova et al, 2010). In SHR, Cd36 was established as a key determinant of the insulin-sensitizing actions of thiazolidinediones using SHR transgenic and congenic strains expressing wild-type Cd36 (Qi et al, 2002).…”