Dataset Information

Succinate mediates inflammation-induced adrenocortical dysfunction

ABSTRACT: Inflammation leads the hypothalamus-pituitary-adrenal (HPA) axis activation and increased production of glucocorticoids, which produced by the adrenal cortex, exert potent anti-inflammatory effects. The use of omics, including proteomics revealed metabolic changes in steroidogenic adrenocortical cells, including downregulation of the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, decreased ATP production and induction of oxidative stress after lipopolysaccharide (LPS)-induced inflammation.

INSTRUMENT(S): timsTOF Pro 2

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Adrenal Gland

SUBMITTER: Evangelia Thanou

LAB HEAD: Ka Wan Li

PROVIDER: PXD036542 | Pride | 2023-07-21

REPOSITORIES: Pride

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Succinate mediates inflammation-induced adrenocortical dysfunction.

Mateska Ivona I Witt Anke A Hagag Eman E Sinha Anupam A Yilmaz Canelif C Thanou Evangelia E Sun Na N Kolliniati Ourania O Patschin Maria M Abdelmegeed Heba H Henneicke Holger H Kanczkowski Waldemar W Wielockx Ben B Tsatsanis Christos C Dahl Andreas A Walch Axel Karl AK Li Ka Wan KW Peitzsch Mirko M Chavakis Triantafyllos T Alexaki Vasileia Ismini VI

eLife 20230714

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 in ...[more]

PMID: 37449973

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Project description:Steroidogenic acute regulatory protein (Star) facilitates cholesterol transfer into the inner mitochondrial membrane in the acute and regulated production of steroid hormones. Mice lacking Star (Star-/-) share the phenotypes with patients with congenital lipoid adrenal hyperplasia such as compromised production of steroid hormones and florid accumulation of cholesterol esters in adrenal glands and gonads. To define specific patterns of molecular changes with disruption of Star, we performed a transcriptome analysis of steroidogenic cells in adrenal glands. We harvested adrenal glands at E17.5 or 18.5 from seven wild-type (Star+/+) mice or four Star-/- mice having the transgene targeting enhanced green fluorescent protein (eGFP) under the control of regulatory sequences of mouse Star gene. Steroidogenic cells were selectively isolated by fluorescent-activated cell sorting. The gene expression profile of the fluorescence-positive cells was obtained with Agilent Whole Mouse Genome Microarray and was confirmed by quantitative real-time PCR. We identified 961 and 622 genes that were significantly up-regulated and down-regulated, respectively, in Star-/- mice compared with Star+/+ mice (fold difference ≥2, p value of Student t test <0.05, and Benjamini-Hochberg false discovery rate of multiple comparison test <0.2). In Star-/- mice, expression levels of genes involved in cholesterol mobilization and efflux or immune response as antigen presenting cells were significantly increased, and transition from fetal to adult adrenocortical cells were significantly decreased, whereas those of genes related to steroid hormone biosynthesis or cholesterol biosynthesis and influx were not significantly changed. The trancriptome analysis revealed hitherto undescribed characteristic changes in adrenocortical cells and expanded our understanding of the pathophysiology of the steroidogenic cells with disruption of Star. Gene expression profiles of isolated adrenal steroidogenic cells were compared between seven wild-type mice and four knockout mice lacking steroidogenic acute regulatory protein at E17.5-18.5.

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