Association of Nuclear Receptor Coactivators with Hypoxia-Inducible Factor-1α in the Serum of Patients with Chronic Kidney Disease.

Nuclear receptor coactivators (NCOAs), consisting of coactivators and corepressors, dramatically enhance the transcriptional activity of nuclear receptors. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays a major role under hypoxic conditions. This study was performed with the focus on the association of NCOAs with HIF-1α in the serum of chronic kidney disease (CKD) patients. Sixty patients with stage 5 CKD and 30 healthy controls from The Second Affiliated Hospital of Shantou University Medical College, between March 21, 2019, and October 30, 2019, were recruited in this prospective cohort study. We analyzed the serum levels of NCOAs (NCOA1, NCOA2, and NCOA3), HIF-1α, vascular endothelial growth factor (VEGF), etc. and assessed whether there was any relationship between these parameters and CKD disease. We found that circulating NCOA1 was positively associated with circulating NCOA2, NCOA3, and HIF-1α. A positive correlation was also observed between NCOA2 and NCOA1, NCOA3, HIF-1α, and VEGF. Furthermore, statistically significant correlations between NCOA3 and NCOA1, NCOA2, and HIF-1α were observed. The serum levels of VEGF in the CKD group were higher than those of the healthy control group. Circulating NCOA1 and circulating NCOA2 were negatively associated with procalcitonin. In conclusion, there was an association between circulating NCOA1, NCOA2, NCOA3, and circulating HIF-1α, and circulating VEGF was a risk factor for CKD disease. However, more studies should be performed to confirm this hypothesis.

Research resource: tissue- and pathway-specific metabolomic profiles of the steroid receptor coactivator (SRC) family.

The rapidly growing family of transcriptional coregulators includes coactivators that promote transcription and corepressors that harbor the opposing function. In recent years, coregulators have emerged as important regulators of metabolic homeostasis, including the p160 steroid receptor coactivator (SRC) family. Members of the SRC family have been ascribed important roles in control of gluconeogenesis, fat absorption and storage in the liver, and fatty acid oxidation in skeletal muscle. To provide a deeper and more granular understanding of the metabolic impact of the SRC family members, we performed targeted metabolomic analyses of key metabolic byproducts of glucose, fatty acid, and amino acid metabolism in mice with global knockouts (KOs) of SRC-1, SRC-2, or SRC-3. We measured amino acids, acyl carnitines, and organic acids in five tissues with key metabolic functions (liver, heart, skeletal muscle, brain, plasma) isolated from SRC-1, -2, or -3 KO mice and their wild-type littermates under fed and fasted conditions, thereby unveiling unique metabolic functions of each SRC. Specifically, SRC-1 ablation revealed the most significant impact on hepatic metabolism, whereas SRC-2 appeared to impact cardiac metabolism. Conversely, ablation of SRC-3 primarily affected brain and skeletal muscle metabolism. Surprisingly, we identified very few metabolites that changed universally across the three SRC KO models. The findings of this Research Resource demonstrate that coactivator function has very limited metabolic redundancy even within the homologous SRC family. Furthermore, this work also demonstrates the use of metabolomics as a means for identifying novel metabolic regulatory functions of transcriptional coregulators.