The Nuclear Receptor Corepressor in the Adrenal Gland Controls the Cell Fate of Aged Adrenocortical Cells
Authors: Zheng Huifei , Huang Chen-Che 
Published: May 2023

The nuclear receptor corepressor 1 (NCoR1) interacts with different nuclear proteins to modulate gene expression. It is ubiquitously expressed in many tissues and has been shown to control the transcriptional activity of several nuclear receptors. In vivo and in vitro studies demonstrated that NCoR1 is an important player in regulating various physiological activities, such as tissue insulin sensitivity, oxidative metabolism, immune response, and cell differentiation. NCoR1 also regulates many pathways, including the thyroid hormone signaling pathway. In the adrenal gland, our previous studies demonstrated that thyroid hormone elicits its function through the thyroid hormone receptor in the inner cortex to regulate the cell fate of this cell population. We found that thyroid hormone treatment delays the cell regression of the mouse adrenal gland inner cortex (the X-zone), a structure that originates from the fetal adrenal gland. During postnatal development, X-zone cells undergo apoptosis and will be replaced by newly formed cells from the stem/progenitor cells in the outer cortex and the capsule. Our transcriptomic study showed that the expression timeline of Ncor1 in the mouse adrenal gland is similar to many adrenal X-zone marker genes. Because NCoR1 is a key corepressor controlling the thyroid hormone signaling pathway and is the major nuclear corepressor expressed in the adrenal gland, we hypothesize that NCoR1 involves in the cell fate regulation of the adrenal X-zone. To further study this ubiquitously expressed corepressor and its function in the adrenal cortex, we conditionally deleted Ncor1 in the adrenal cortex by crossing the Ncor1 floxed mice with the steroidogenic factor 1 (SF1) Cre mice. The Ncor1;Sf1-Cre mice ( Ncor1 cKO mice) are viable. Both male and female cKO mice are fertile. Immunostaining showed a delayed regression of the inner cortex in male Ncor1 cKO mice. Whereas in female cKO mice, the inner cortex is thicker compared to their wild-type littermates. Interestingly, the RNA sequencing analysis revealed that the top differentially expressed genes were highly related to lipid metabolism with the upregulation of 24-dehydrocholesterol reductase ( Dhcr24), a key gene that controls cholesterol synthesis. We further found that the X-zone regression was accelerated in Dhcr24 conditional knockout mice. In summary, our finding indicates that the NCoR1-regulated lipid homeostasis is linked to the cell fate of the adrenal gland inner cortex. This result helps decipher the connection between the cell–protective effect and the lipid metabolic reprogramming, a hallmark of many developmental events and disease progression such as cancer aggressiveness. Acknowledgments: This study is supported by NIH R00 HD082686 and R03 AG065518 to CJH. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.