Multi-Omics Analysis Reveals Up-Regulation of APR Signaling, LXR/RXR and FXR/RXR Activation Pathways in Holstein Dairy Cows Exposed to High-Altitude Hypoxia

SIMPLE SUMMARY: Blood has been widely collected and analyzed for diagnosing and monitoring diseases in human beings and animals. A range of plasma proteins and peptides were set as biomarkers for pathological and physiological status. Previous researchers have explored how humans, pigs, dogs, and horses adapt to hypoxia at high altitudes. Additionally, the mechanism of hypoxia adaptation in human, mice, and shrimp was studied by proteomics. However, information on the adaptation mechanism of Holstein cows introduced to high altitudes is limited. The present study was conducted to the adaptation mechanism of Holstein dairy cows to high-altitude hypoxia by miRNA microarray analysis and the isobaric tags for relative and absolute quantitation (iTRAQ) iTRAQ technology. Based on the obtained results, Holstein dairy cows transported to Nyingchi may adapt to the high-altitude hypoxia through regulation of inflammatory homeostasis by up-regulating the acute phase response (APR) APR and activation of the liver X receptor/retinoid X receptor (LXR/RXR)LXR/RXR and farnesoid X receptor/ retinoid X receptor (FXR/RXR) FXR/RXR pathways. ABSTRACT: Changes in the environment such as high-altitude hypoxia (HAH) high-altitude hypoxia can lead to adaptive changes in the blood system of mammals. However, there is limited information about the adaptation of Holstein dairy cows introduced to high-altitude areas. This study used 12 multiparous Holstein dairy cows (600 ± 55 kg, average three years old) exposed to HAH conditions in Nyingchi of Tibet (altitude 3000 m) and HAH-free conditions in Shenyang (altitude 50 m). The miRNA microarray analysis and iTRAQ proteomics approach (accepted as more suitable for accurate and comprehensive prediction of miRNA targets) were applied to explore the differences in the plasma proteomic and miRNA profiles in Holstein dairy cows. A total of 70 differential miRNAs (54 up-regulated, Fold change (FC) FC > 2, and 16 down-regulated, FC < 0.5) and 226 differential proteins (132 up-regulated, FC > 1.2, and 94 down-regulated, FC < 0.8) were found in the HAH-stressed group compared with the HAH-free group. Integrative analysis of proteomic and miRNA profiles demonstrated the biological processes associated with differential proteins were the immune response, complement activation, protein activation, and lipid transport. The integrative analysis of canonical pathways were most prominently associated with the APR signaling (z = 1.604), and LXR/RXR activation (z = 0.365), and FXR/RXR activation (z = 0.446) pathways. The current results indicated that Holstein dairy cows exposed to HAH could adapt to high-altitude hypoxia by up-regulating the APR, activating the LXR/RXR and FXE/RXR pathways.