Severe Heat Stress Modulated Nuclear Factor Erythroid 2-related Factor 2 and Macrophage Migration Inhibitory Factor Pathway in Rat Liver

Heat stress impairs physiology and overall functionality of the body at tissue and organ level in animals. Liver being a vital organ performs more than hundreds regulatory functions of the body. Present study investigates the modulation of molecular pathways that are responsible for liver damage triggered by heat stress. Male Sprague dawley rats were exposed to heat stress (45 °C) in heat simulation chamber till core temperature reaches 40 °C and 42 °C in 25 and 42 min respectively. For in-depth evaluation of liver functions during severe heat stress, hepatic transcriptome and proteome were analysed by microarray and two dimensional gel electrophoresis respectively. Results revealed major alterations in redox status, inflammation, mitochondrial dysfunction and proteostasis related pathways. Data of molecular pathway analysis demonstrate that nuclear factor erythroid 2-related factor 2 (NRF-2) mediated oxidative stress response and macrophage migration inhibitory factor (MIF) regulated inflammatory pathways were upregulated in severe heat stressed liver. Expression levels of downstream molecules of above pathways such as heat shock protein 90AB 1, peroxiredoxin 5, Jun N-terminal kinases 1/2, heme-oxygenase 1, apolipoprotein 1 and interleukin 10 were examined and result suggested the upregulation of these genes modulates the NRF-2 and MIF regulated pathways in heat stressed liver. Irregularity in molecular signalling networks lead to mitochondrial dysfunction indicated by upregulation of ATP synthase β and peroxiredoxin 1 along with decreased levels of glucose-6-phosphate dehydrogenase and enhanced activity of cytochrome c in liver mitochondria. Thus, current study demonstrated heat induced alterations in key liver functions were regulated by NRF-2 and MIF pathways.