ZBTB32 performs crosstalk with the glucocorticoid receptor and is crucial in glucocorticoid responses to starvation
| Autor: | Geert van Loo, Rudi Beyaert, Kelly Van Looveren, Roman Vangoitsenhoven, Tineke Vanderhaeghen, Bart Van der Schueren, Jan Tavernier, Toshinori Nakayama, Sylviane Dewaele, Charlotte Wallaeys, Steven Timmermans, Claude Libert, Leen Catrysse, Lise Van Wyngene, Melanie Eggermont, Ioanna Petta, Katrien Corbeels, Jolien Vandewalle, Karolien De Bosscher |
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| Rok vydání: | 2021 |
| Předmět: |
PROTEINS
DNA-BINDING Science Biology Article MECHANISMS Endocrinology Glucocorticoid receptor DOMAIN Downregulation and upregulation Medicine and Health Sciences medicine Transcription factor Zinc finger Starvation Multidisciplinary IDENTIFICATION biological sciences Biology and Life Sciences SR-BI GENE Cell biology ALPHA GR animal physiology Crosstalk (biology) Cholesterol import physiology medicine.symptom Glucocorticoid SCAVENGER RECEPTOR medicine.drug |
| Zdroj: | iScience, Vol 24, Iss 7, Pp 102790-(2021) ISCIENCE iScience |
| ISSN: | 2589-0042 |
| Popis: | Summary The hypothalamic-pituitary-adrenal (HPA) axis forms a complex neuroendocrine system that regulates the body’s response to stress such as starvation. In contrast with the glucocorticoid receptor (GR), Zinc finger and BTB domain containing 32 (ZBTB32) is a transcription factor with poorly described functional relevance in physiology. This study shows that ZBTB32 is essential for the production of glucocorticoids (GCs) in response to starvation, since ZBTB32−/− mice fail to increase their GC production in the absence of nutrients. In terms of mechanism, GR-mediated upregulation of adrenal Scarb1 gene expression was absent in ZBTB32−/− mice, implicating defective cholesterol import as the cause of the poor GC synthesis. These lower GC levels are further associated with aberrations in the metabolic adaptation to starvation, which could explain the progressive weight gain of ZBTB32−/− mice. In conclusion, ZBTB32 performs a crosstalk with the GR in the metabolic adaptation to starvation via regulation of adrenal GC production. Graphical abstract Nutrient shortage is sensed by the brain and causes the activation of the HPA axis. The synthesis and release of corticosterone by the adrenal glands is stimulated via the release of ACTH. Cholesterol, the precursor of corticosterone, is imported into the adrenal cortex cells via high-density lipoproteins (HDLs) which are internalized via the SR-B1 (Scarb1) receptor. ZBTB32 acts as a GR co-activator by enhancing the GR-induced upregulation of Scarb1 gene expression and thereby controlling the cholesterol import into the adrenal glands during food deprivation. The expression of Scarb1 is positively regulated by corticosterone and the GR agonist dexamethasone. Furthermore, corticosterone is also responsible for the metabolic adaptations of mice during starvation, by inducing lipolysis in the white adipose tissue (WAT) thereby releasing glycerol and free fatty acids into the bloodstream. Glycerol will then be used as a precursor for gluconeogenesis in the liver, while the FFAs will induce PPARα signaling in the liver. Lower corticosterone levels in ZBTB32−/− mice are associated with disturbances in the metabolic adaptation to starvation, including lower lipolytic activity of WAT and aberrant PPARα signaling in the liver, which could result in weight gain and fat mass accumulation in ZBTB32−/− mice over time. Highlights • ZBTB32 is involved in the glucocorticoid production in response to starvation • GR-mediated upregulation of adrenal Scarb1 regulates cholesterol import • The weight gain of ZBTB32−/− mice is associated with aberrant metabolic adaptations Biological sciences; physiology; animal physiology; Endocrinology |
| Databáze: | OpenAIRE |
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