Succinate mediates inflammation-induced adrenocortical dysfunction

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

Abstract

The hypothalamus-pituitary-adrenal (HPA) axis is activated in response to inflammation leading to increased production of anti-inflammatory glucocorticoids by the adrenal cortex, thereby representing an endogenous feedback loop. However, severe inflammation reduces the responsiveness of the adrenal gland to adrenocorticotropic hormone (ACTH), although the underlying mechanisms are poorly understood. Here, we show by transcriptomic, proteomic, and metabolomic analyses that LPS-induced systemic inflammation triggers profound metabolic changes in steroidogenic adrenocortical cells, including downregulation of the TCA cycle and oxidative phosphorylation, in mice. Inflammation disrupts the TCA cycle at the level of succinate dehydrogenase (SDH), leading to succinate accumulation and disturbed steroidogenesis. Mechanistically, IL-1β reduces SDHB expression through upregulation of DNA methyltransferase 1 (DNMT1) and methylation of the SDHB promoter. Consequently, increased succinate levels impair oxidative phosphorylation and ATP synthesis and enhance ROS production, leading to reduced steroidogenesis. Together, we demonstrate that the IL-1β-DNMT1-SDHB-succinate axis disrupts steroidogenesis. Our findings not only provide a mechanistic explanation for adrenal dysfunction in severe inflammation, but also offer a potential target for therapeutic intervention.

Details

OriginalspracheEnglisch
Aufsatznummere83064
Seitenumfang34
FachzeitschrifteLife
Jahrgang12(2023)
PublikationsstatusVeröffentlicht - 14 Juli 2023
Peer-Review-StatusJa

Externe IDs

PubMed 37449973

Schlagworte

Fächergruppen, Lehr- und Forschungsbereiche, Fachgebiete nach Destatis

Schlagwörter

  • adrenal gland, cell biology, DNMT1, glucocorticoids, IL-1β, immunology, inflammation, mouse, succinate, succinate dehydrogenase, Adrenocorticotropic Hormone/metabolism, Glucocorticoids/metabolism, Inflammation/metabolism, Succinic Acid, Animals, Proteomics, Mice

Bibliotheksschlagworte