AMPK Deletion in the Intestinal Epithelium Reveals Region‐Specific Roles in Health and Disease
Notice bibliographique
Résumé
AMP‐Activated Protein Kinase (AMPK) is a conserved energy sensor that has been suggested to modulate intestinal barrier function. Intestinal barrier function contributes to partitioning of the gut lumen and lamina propria and is primarily mediated by intestinal epithelial cell (IEC) control of permeability, ion transport, and regulation of cell turnover. Dysfunction of the intestinal barrier is a feature of pathologies such as Inflammatory Bowel Disease (IBD) and diarrhea. The aim of this study was to identify the impact of AMPK activity on intestinal barrier function by utilizing a tissue‐specific knockout mouse model lacking both AMPK‐α catalytic isoforms. Methods Intestinal epithelial‐specific AMPK knockout mice (AMPKα Δ IEC KO ) were created by crossing Prkaa1 and Prkaa2 floxed mice (AMPKα fl/fl ) with Villin‐Cre mice. Large intestine (cecum, proximal, and distal colon) was stripped of the seromuscular layer and mounted in Ussing chambers containing Kreb’s Ringer’s buffer. Transepithelial electrical resistance (TER), 4 kDa FITC‐dextran (FD4) permeability and ion transport responses to Forskolin (20 μM, bilateral) and Carbachol (300 μM, serosal) were measured. Protein expression was analyzed in isolated IECs or whole tissue by immunoblotting or by immunostaining of whole intestinal tissue. Colitis was induced by 5% Dextran Sodium Sulfate (DSS) in drinking water (ad libitum for 5 days) followed by 3 days of water. Results AMPKα Δ IEC KO mice had decreased TER only in the proximal colon vs. AMPKα fl/fl mice (p = 0.057, n = 6–7), with no change in FD4 permeability. Decreased TER in the proximal colon was associated with reduced Claudin‐4 expression. Claudin‐4 in the distal colon was significantly decreased in AMPKα Δ IEC KO mice (48% decrease, p = 0.0136, n = 5). Ion transport responses to Carbachol were increased in the cecum of AMPKα Δ IEC KO mice vs . AMPKα fl/fl mice (p = 0.012, n = 3), while Forskolin responses were unchanged. Expression of the AMPK‐regulated ion transport protein, Na + ‐K + ‐Cl − Cotransporter 1 (NKCC1) was increased in the cecum and distal colon of AMPKα Δ IEC KO vs . AMPKα fl/fl mice, thus indicating that AMPK repressed NKCC1 expression in these regions (p<0.05 ‐ p<0.001). Inflammatory challenge (DSS colitis) caused increased cell death (TUNEL staining) in cecum and distal colon but TUNEL staining was reduced in the cecum of AMPKα Δ IEC KO mice vs . AMPKα fl/fl mice (6.2‐fold, p = 0.0241, n = 2–3). Consistent with unaltered TUNEL staining in the proximal colon, the apoptosis markers cleaved caspase‐3 and PARP‐1 were also reduced in both mouse genotypes. However, despite increased TUNEL staining, these cleavage events were not increased in the cecum or distal colon of DSS‐treated mice suggesting cell death occurred by a mechanism independent of caspase‐3 and PARP cleavage. Conclusions Epithelial AMPK regulation of intestinal barrier permeability, ion transport, and inflammation‐induced cell death displays regional heterogeneity along the large intestine. Support or Funding Information NIH 2R01DK091281 (DFM)
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».