Disrupted pancreatic exocrine differentiation and malabsorption in response to chronic elevated systemic glucocorticoid.
Glucocorticoids are antiinflammatory therapeutics that have potent effects on cell differentiation. The aim of this study was to establish whether systemic glucocorticoid exposure significantly affects pancreatic differentiation in vivo because hepatocyte-like cells have been documented to occur in the diseased rodent pancreas. Expression of hepatic markers was examined in pancreata from mice genetically modified to secrete elevated circulating endogenous glucocorticoid [Tg(Crh)]. Tg(Crh) mice with elevated glucocorticoid appeared cushingoid and by 21 weeks of age were obese, insulin-resistant, and had extensive areas of hepatic gene expression in exocrine tissue. Acinar cells from Tg(Crh) mice costained for both amylase and cyp2e1, suggesting direct acinar-hepatic transdifferentiation. Hepatic expression increased with age in the pancreas to such an extent that malabsorption and rapid weight loss occurred in a subset of aging mice; this effect was reversed by dietary porcine pancreatic enzyme supplementation. Indeed, pancreatic expression of hepatic markers was prevented by adrenalectomy, establishing a direct role for glucocorticoid. Elevated levels of circulating glucocorticoid therefore promote a transdifferentiation of adult exocrine pancreas into hepatocyte-like cells, and chronic exposure results in pancreatic malfunction. Glucocorticoids are thus capable of modulating the differentiation of terminally differentiated adult cells.
Wallace
Karen
K
Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
Flecknell
Paul A
PA
Burt
Alastair D
AD
Wright
Matthew C
MC
D000315:Adrenalectomy; D000367:Age Factors; D000818:Animals; D001786:Blood Glucose; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005938:Glucocorticoids / Q000097:blood*; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D007328:Insulin / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001786:Blood Glucose; D005938:Glucocorticoids; D007328:Insulin; D003346:Corticotropin-Releasing Hormone