PPARγ co-activator-1α co-activates steroidogenic factor 1 to stimulate the synthesis of luteinizing hormone and aldosterone

Abstract

The orphan nuclear receptor SF-1 (steroidogenic factor 1) is highly expressed in the pituitary, gonad and adrenal glands and plays key roles at all levels of the hypothalamic-pituitary-steroidogenic tissue axis. In the present study, we show that PGC-1α [PPARγ (peroxisome-proliferator-activated receptor γ) co-activator 1α] interacts with and co-activates SF-1 to induce LHβ (luteinizing hormone β) and αGSU (α-glycoprotein subunit) gene expression, subsequently leading to the increased secretion of LH in pituitary gonadotrope-derived αT3-1 cells. PGC-1α co-activation of LHβ expression requires an SF-1-binding element [GSE (gonadotrope-specific element)] mapped to the promoter region of LHβ. Mammalian two-hybrid and co-immunoprecipitation assays, as well as GST (glutathione transferase) pull-down experiments demonstrated that PGC-1α interacts with SF-1 in vivo and in vitro. Additionally, PGC-1α stimulates the expression of Cyp11b2 (aldosterone synthase gene), Cyp11b1 (steroid 11β-hydroxylase gene) and P450scc (cholesterol side-chain cleavage enzyme), and the synthesis of aldosterone in adrenal-cortex-derived Y-1 cells. Chromatin immunoprecipitation assays confirmed that endogenous PGC-1α co-localizes with SF-1 in the LHβ and Cyp11b2 promoter region. Knockdown of endogenous SF-1 by siRNA (small interfering RNA) abolished the PGC-1α induction of LHβ and Cyp11b2 gene expression in αT3-1 and Y-1 cells respectively. Finally, we demonstrated that PGC-1α induces SF-1 gene expression in both αT3-1 and Y-1 cells. Taken together, our findings reveal the potential role of PGC-1α and suggest that it may play important roles in steroidogenesis, gonad development and sex differentiation through SF-1.

Aldosterone Inactivates the Endothelin-B Receptor via a Cysteinyl Thiol Redox Switch to Decrease Pulmonary Endothelial Nitric Oxide Levels and Modulate Pulmonary Arterial Hypertension

“…Our observation that CYP11B2 expression was increased via upregulation of PGC-1α and its association with SF at the promoter region of the CYP11B2 gene confirms prior work in adrenal cortex-derived Y1 cells that demonstrated a similar mechanism of CYP11B2 upregulation. 15 We were also able to provide additional evidence for this mechanism by PGC-1α agonism with the thiazolidinedione, pioglitazone. Notwithstanding this finding, the relationship between thioglitazone/PGC-1α and aldosterone remains unresolved.…”

“…In adrenal cortical Y-1 cells, the transcription factor PPAR-γ co-activator-1α (PGC-1α) interacts with the nuclear receptor protein steroidogenesis factor-1 (SF) to regulate CYP11B2 gene transcription and induce aldosterone synthesis. 15 Therefore, to determine if ET-1 increased aldosterone synthase protein levels by this mechanism in HPAECs, we first explored the effect of ET-1 on PGC-1α and SF protein expression levels in these cells. Compared to V-treated cells, exposure to ET-1 (1, 10, 100 nM) for 24 h induced a concentration-dependent increase in PGC-1α protein expression levels (176.…”

Blimp-1 impairs T cell function via upregulation of TIGIT and PD-1 in patients with acute myeloid leukemia

“…ChIP assays were conducted as previously described [33]. Briefly, T cells were stimulated in vitro with anti-CD3 [34] for 48 h followed by cross-linking, sonication, and chromatin immunoprecipitation with antibodies to Blimp-1 or normal goat IgG (Abcam, Cambridge, UK).…”

Dysfunction of the PGC-1α-mitochondria axis confers adriamycin-induced podocyte injury

“…PGC-1␣ is a transcriptional coactivator of PPAR-␥ and other nuclear hormones (13,30,42). Repression of PGC-1␣ caused abnormal mitochondrial morphology and downregulation of mitochondria-related enzymes (6).…”