Interleukin 6 modulates PPARα and PGC-1α and is involved in high-fat diet induced cardiac lipotoxicity in mouse

Background: Interleukin 6 (IL-6) may be involved in regulation of cardiac lipid metabolism and mitochondrial function through its influence on peroxisome proliferator-activated receptors (PPARs). In this study we evaluated the impact of the physiological level of IL-6 on the expression of PPAR alpha and PGC-1 alpha in the heart and the effect of lack of this cytokine on high-fat diet (HFD) induced lipotoxicity. Methods: Male C57BL6/J wild type (WT) and IL-6 knock-out (IL-6KO) mice were used. 20 animals of each genotype were fedwith HFD for 15-18 weeks. Cardiac function was assessed using echocardiography and cardiomyocyte ultrastructure was examined using electron microscopy. QT-PCR and Western blotting were applied to estimate the expression of PPAR alpha and PGC-1 alpha at the transcriptional and protein levels. Results: At baseline WT and IL-6KO mice had similar size and function of the left ventricle. HFD induced similar left ventricular hypertrophic response in both groups without causing heart failure, but only WT animals had increased resting ejection fraction of the LV. Ultrastructure of HFD groups showed markers of lipotoxicity, that were more pronounced in IL-6KO group. In basal conditions IL-6KO animals had lower PPAR alpha and similar PGC-1 alpha expression as compared to WT. HFD induced downregulation of both PPAR alpha and PGC-1 alpha in WT animals, while in IL-6KO mice this effect was constrained. Conclusion: IL-6 is involved in basal regulation of PPAR alpha and PGC-1 alpha expression in cardiomyocytes. The lack of this cytokine promotes high-fat diet induced lipotoxicity but without overt manifestations of cardiac failure. (C) 2016 Elsevier Ireland Ltd. All rights reserved.