9225 Reduced Alpha-1 Antitrypsin Activity Is Associated with Higher Plasma Free Cortisol and Increased Tissue Glucocorticoid Exposure in Humans in vivo
Bibliographic record
Abstract
Abstract Disclosure: L.D. Boyle: None. M. Nixon: None. C.M. Underhill: None. L.A. Hill: None. N.Z. Homer: None. M. Magennis: None. R. Andrew: None. G.L. Hammond: None. J.G. Lewis: None. R.H. Stimson: None. B.R. Walker: None. Background Corticosteroid Binding Globulin (CBG) binds >85% of plasma cortisol, modulating its biological activity. Proteolytic cleavage by neutrophil elastase (NE) reduces CBG binding capacity, proposed to increase free cortisol availability to inflamed tissues. Genetic variation at the locus spanning SERPINA1 (encoding alpha-1 antitrypsin, AAT, the endogenous inhibitor of NE) and SERPINA6 (CBG) altered morning total plasma cortisol. We hypothesised that AAT deficiency increased CBG cleavage and hence free plasma cortisol, resulting in amplified tissue cortisol delivery and increased HPA axis negative feedback. We tested this in recall-by-genotype studies of people who are heterozygous for inactivating mutations in SERPINA1. Methods 16 asymptomatic carriers of deleterious SERPINA1 single nucleotide polymorphisms (rs17580 & rs28929474) and 16 age-, gender- and BMI-matched controls were recruited from the Generation Scotland Biobank. To quantify in vivo whole body glucocorticoid appearance and clearance rates, and estimate tissue cortisol uptake, we performed arterio-venous plasma sampling across abdominal adipose and skeletal muscle during steady-state 9,11,12,12-[2H]4-cortisol tracer infusion. To assess endogenous negative feedback, participants underwent combined receptor antagonist stimulation of the HPA axis (‘CRASH’) testing using RU486 and spironolactone, or placebo in a double blind randomised crossover design. Total cortisol (LC-MS/MS), free cortisol (isotopic dilution & ultrafiltration), CBG binding capacity (radioligand displacement), CBG concentration and AAT (ELISA) were measured in plasma. Tissue cortisol (LC-MS/MS) and glucocorticoid-dependent transcripts (qPCR) were measured in adipose biopsy samples collected at end of study. Results AAT was ∼30% lower in AAT+/- (p=0.0002 vs control). Plasma CBG concentration, binding capacity and total cortisol were similar between groups. However, plasma free cortisol fraction was higher in AAT+/- subjects (16.1 +/- 0.2 vs 13.9 +/- 0.04 %, p<0.0001). Adipose tissue from AAT+/- subjects displayed increased cortisol levels and increased glucocorticoid-responsive transcripts PER1 and LPL compared to controls. Consistent with release from CBG, total and free cortisol release across skeletal muscle was increased in AAT+/- subjects vs controls. The rate of appearance of 9,12,12-[2H]3-cortisol was reduced in AAT+/- (p=0.03 vs control), consistent with decreased whole body 11β-HSD1 activity. CRASH testing did not reveal additional differences between groups. Discussion Subclinical AAT deficiency is associated with a higher free cortisol fraction and increased tissue glucocorticoid exposure. Although consistent with the hypothesis of local tissue-mediated control of glucocorticoid exposure via the NE/AAT/CBG axis, these findings were not accompanied by measurable changes in CBG. Presentation: 6/3/2024
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".