Plasma 1H NMR-based metabolomic analysis reveals the lipid regulating effect of novel carboxamide derivatives in hyperlipidemic rats.

BACKGROUND

Hyperlipidemia refers to the abnormal elevation in the levels of one or more plasma lipids and lipoproteins.

AIMS: The purpose of this study is to examine the underlying changes in metabolic pathways associated with the lipid-lowering activity of novel carboxamide derivatives.

METHODS

Hyperlipidemia was induced in male Wistar rats by the administration of Triton WR-1339. Carboxamide derivatives, N-(3-benzoylphenyl) - 5-nitrofuran- 2-carboxamide (Compound A) and N-(4-acetylphenyl) - 5-nitrofuran- 2-carboxamide (Compound B) were administered intragastrically and their activity was compared to the lipid-lowering drug fenofibrate. Metabolic analysis of plasma samples was done using proton nuclear magnetic resonance spectrometer equipped with a cryogenic probe. Moreover, expression levels of related genes were analyzed in liver, kidney and heart tissues using qPCR.

RESULTS

The tested carboxamide compounds A and B significantly reduced the elevated plasma triglycerides levels by 83% and 68%, respectively. Metabolomic analysis results revealed the impact of carboxamide compounds on the levels of 22 potential biomarkers. Carboxamide compounds partially restored the dysregulated levels of the differential metabolites and reversed the metabolic disturbance induced in hyperlipidemic rats. These results were comparable to those observed in the fenofibrate group. Carboxamide compounds activity was attributed to the regulation of not only lipid metabolism but also energy metabolism, purine metabolism and amino acid metabolism. Moreover, metabolomic results were connected to the expression of related genes in different tissues. Carboxamide compounds were able to restore gene expression levels of related genes, upregulating SDHA expression in liver, SLC13A3 and SDHA in kidney, along with upregulating SLC5A3 expression and downregulating SLC25A10 in the heart.

CONCLUSION

Overall, based on the lipid profile results and metabolic analysis supported by molecular analysis, both carboxamide derivatives showed promising lipid-lowering activity and displayed regulatory activity of metabolic pathways that were disturbed by hyperlipidemia induction. The efficacy of carboxamide compounds was comparable to the conventional lipid-lowering drug, fenofibrate. Compound A exhibited superior activity significantly lowering triglycerides levels and restoring many of the metabolic alterations induced in hyperlipidemia.