Aldo Keto Reductase 1B7 and Prostaglandin F2α Are Regulators of Adrenal Endocrine Functions

Prostaglandin F2α (PGF2α), represses ovarian steroidogenesis and initiates parturition in mammals but its impact on adrenal gland is unknown. Prostaglandins biosynthesis depends on the sequential action of upstream cyclooxygenases (COX) and terminal synthases but no PGF2α synthases (PGFS) were functionally identified in mammalian cells. In vitro, the most efficient mammalian PGFS belong to aldo-keto reductase 1B (AKR1B) family. The adrenal gland is a major site of AKR1B expression in both human (AKR1B1) and mouse (AKR1B3, AKR1B7). Thus, we examined the PGF2α biosynthetic pathway and its functional impact on both cortical and medullary zones. Both compartments produced PGF2α but expressed different biosynthetic isozymes. In chromaffin cells, PGF2α secretion appeared constitutive and correlated to continuous expression of COX1 and AKR1B3. In steroidogenic cells, PGF2α secretion was stimulated by adrenocorticotropic hormone (ACTH) and correlated to ACTH-responsiveness of both COX2 and AKR1B7/B1. The pivotal role of AKR1B7 in ACTH-induced PGF2α release and functional coupling with COX2 was demonstrated using over- and down-expression in cell lines. PGF2α receptor was only detected in chromaffin cells, making medulla the primary target of PGF2α action. By comparing PGF2α-responsiveness of isolated cells and whole adrenal cultures, we demonstrated that PGF2α repressed glucocorticoid secretion by an indirect mechanism involving a decrease in catecholamine release which in turn decreased adrenal steroidogenesis. PGF2α may be regarded as a negative autocrine/paracrine regulator within a novel intra-adrenal feedback loop. The coordinated cell-specific regulation of COX2 and AKR1B7 ensures the generation of this stress-induced corticostatic signal

Cushing's Syndrome and Fetal Features Resurgence in Adrenal Cortex–Specific Prkar1a Knockout Mice

Carney complex (CNC) is an inherited neoplasia syndrome with endocrine overactivity. Its most frequent endocrine manifestation is primary pigmented nodular adrenocortical disease (PPNAD), a bilateral adrenocortical hyperplasia causing pituitary-independent Cushing's syndrome. Inactivating mutations in PRKAR1A, a gene encoding the type 1 α-regulatory subunit (R1α) of the cAMP–dependent protein kinase (PKA) have been found in 80% of CNC patients with Cushing's syndrome. To demonstrate the implication of R1α loss in the initiation and development of PPNAD, we generated mice lacking Prkar1a specifically in the adrenal cortex (AdKO). AdKO mice develop pituitary-independent Cushing's syndrome with increased PKA activity. This leads to autonomous steroidogenic genes expression and deregulated adreno-cortical cells differentiation, increased proliferation and resistance to apoptosis. Unexpectedly, R1α loss results in improper maintenance and centrifugal expansion of cortisol-producing fetal adrenocortical cells with concomitant regression of adult cortex. Our data provide the first in vivo evidence that loss of R1α is sufficient to induce autonomous adrenal hyper-activity and bilateral hyperplasia, both observed in human PPNAD. Furthermore, this model demonstrates that deregulated PKA activity favors the emergence of a new cell population potentially arising from the fetal adrenal, giving new insight into the mechanisms leading to PPNAD

Dose optimization a major challenge for acceptability of nuclear medicine

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Sterols in various organs of adult female swine

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Modalités de l'absorption intestinale du cholestérol chez le porc

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Irradiation accidentelle et reconstitution lymphocytaire T : données récentes et perspectives

Les lymphocytes T sont l'une des populations les plus radiosensibles de l'organisme. La reconstitution des lymphocytes T est lente, et des déficits quantitatifs et qualitatifs apparaissent à long terme chez les personnes irradiées. Les mécanismes de la reconstitution lymphocytaire T sont mal connus, et en particulier le rôle joué par le thymus dans cette reconstitution reste peu clair. Le thymus est l'organe lymphode primaire dans lequel se différencie l'ensemble des populations lymphocytaires T durant la vie foetale et post-natale. Le thymus a été considéré pendant longtemps comme étant inactif à l'age adulte. Cependant, des données récentes montrent que le thymus reste, au moins en partie, fonctionnel à l'age adulte. Ceci suggère un rôle important du thymus dans l'homostasie des populations lymphocytaires T, mais aussi dans la reconstitution des lymphocytes T aprés irradiation, y compris à l'age adulte. Par ailleurs, des études récentes révèlent que les effets des rayonnements ionisants sont, au moins en partie, responsables des déficits quantitatifs des lymphocytes T observés à long terme après irradiation. Ces données montrent la nécessité de poursuivre l'étude des effets des rayonnements ionisants sur le thymus, en particulier par la recherche de bio-indicateurs du fonctionnement du thymus en situation physiologique normale, mais aussi en situation physiopathologique d'irradiation accidentelle

Modes of intestinal cholesterol absorption in adult sows

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