| Popis: |
Historically, bilirubin (BR), the byproduct of broken-down red blood cells, has been perceived exclusively as a toxic substance. Extremely high BR levels have been associated with a variety of diseases including kernicterus, liver disease, hepatitis, pancreatic cancer, gallbladder disorders, and others. However, recent studies have illustrated that moderately elevated BR levels have health benefits. Furthermore, BR is a binding partner to the nuclear receptor PPAR-α, indicating it functions as a hormone. Given PPAR-α’s complex and diverse nature of signaling as a regulator of gene transcription, it makes one wonder how BR might be signaling through this molecule, and if this signaling explains BR’s elusive contribution to various pathologies and health benefits. Here we examined how BR modifies coregulator interactions that regulate signaling pathways. To assess coregulator recruitment, we used a unique coregulator microarray assay called the MARCoNI (Microarray assay for real-time coregulator-nuclear receptor interaction) with purified PPAR-α and cell lysates from systems with elevated BR activity. We also utilized RNA-Sequencing of HepG2 cells treated with biliverdin (which gets rapidly converted to bilirubin within the cell) in order to analyze modification in regulation of cellular pathways. Finally, comparisons were made between pathway analyses of the RNA-sequencing and pathway analyses of BR/PPAR-α-dependent coregulator genes. We identify 17 coregulators with uniquely modified recruitment by bilirubin, along with numerous significant pathways pertaining to development/morphogenesis, cell differentiation, unfolded protein response, immune response, and other biological systems. |
