Disrupted Pancreatic Exocrine Differentiation and Malabsorption in Response to Chronic Elevated Systemic Glucocorticoid

Wallace, Karen; Flecknell, P. A.; Burt, Alastair D.; Wright, Matthew C.

doi:10.2353/ajpath.2010.100107

Cited by 20 publications

(26 citation statements)

References 25 publications

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“…The latter model is supported by our recent observation that hepatocytes appear within the rodent pancreas after a relatively short period of elevated glucocorticoid treatment . Furthermore, in a transgenic mouse model of sustained elevated circulating glucocorticoid levels, the exocrine pancreas transdifferentiates into hepatocyte-like tissue and mice begin to malabsorb and lose weight, an effect reversed by feeding mice with pancreatic porcine enzymes (Wallace et al, 2010). Thus, hepatocytes appear in the pancreas not only after extensive damage (Rao et al, 1988;Yeldandi et al, 1990;Krakowski et al, 1999;Yamaoka et al, 2002) or following overexpression of certain growth factors (Krakowski et al, 1999;Yamaoka et al, 2002), but also in response to elevated glucocorticoid levels.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid-dependent transdifferentiation of pancreatic progenitor cells into hepatocytes is dependent on transient suppression of WNT signalling

et al. 2010

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SummaryDevelopmentally, the pancreas and liver are closely related and pathological conditions -including elevated glucocorticoid levelsresult in the appearance of hepatocytes in the pancreas. The role of the WNT signalling pathway in this process has been examined in the model transdifferentiating pancreatic acinar AR42J-B-13 (B-13) cell. Glucocorticoid treatment resulted in a transient loss of constitutive WNT3a expression, phosphorylation and depletion of -catenin, loss of -catenin nuclear localisation, and significant reductions in T-cell factor/lymphoid enhancer factor (Tcf/Lef) transcriptional activity before overt changes in phenotype into hepatocytelike (B-13/H) cells. A return to higher Tcf/Lef transcriptional activity correlated with the re-expression of WNT3a in B-13/H cells. -catenin knock down alone substituted for and enhanced glucocorticoid-dependent transdifferentiation. Overexpression of a mutant -catenin (pt-X-cat) protein that blocked glucocorticoid-dependent suppression of Tcf/Lef activity resulted in inhibition of transdifferentiation. A small-molecule activator of Tcf/Lef transcription factors blocked glucocorticoid-dependent effects, as observed with pt-X-cat expression. Quercetin -a Tcf/Lef inhibitor -did not promote transdifferentiation into B-13/H cells, but did potentiate glucocorticoid-mediated transdifferentiation. These data demonstrate that the transdifferentiation of B-13 cells into hepatocyte-like cells in response to glucocorticoid was dependent on the repression of constitutively active WNT signalling.

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Section: Discussionmentioning

confidence: 99%

Glucocorticoid-dependent transdifferentiation of pancreatic progenitor cells into hepatocytes is dependent on transient suppression of WNT signalling

et al. 2010

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“…2A. In the Tg(Crh) mouse model of Cushing's disease, which results in widespread expression of hepatocyte-specific gene expression in the acinar pancreas by 21 weeks of age (Wallace et al, 2010b), Sgk1c was also induced from undetectable levels in the pancreas (Fig. 2B).…”

Section: Sgk1 Is Induced By Dex Treatment In B-13 Cellsmentioning

confidence: 93%

“…Tg(Crh) transgenic mice overexpressing a rat corticotrophin releasing factor transgene that results in chronic elevated circulating glucocorticoid and Cushing's disease (Stenzel-Poore et al, 1992;Wallace et al, 2010b) were obtained from the Jackson 411 Role for SGK1 in transdifferentiation hSGK1A KD mutant pFLAG-CMV2 SGK1A-K127M. SGK1A sequence mutated at residue 127.…”

Section: Animalsmentioning

confidence: 99%

“…Administration of glucocorticoid to rats results in the appearance of hepatocytes in the pancreas ). In mice with elevated levels of circulating glucocorticoid, extensive areas of the exocrine (acinar) pancreas express hepatocyte markers, suggestive of widespread acinar transdifferentiation to hepatocytes (Wallace et al, 2010b). This pathological response of acinar cells to elevated glucocorticoid in vivo also occurs to a limited degree in primary cultures of rat acinar cells (Lardon et al, 2004) and efficiently in the AR42J-B-13 (B-13) rat pancreatic exocrine cell line (Shen et al, 2000;Marek et al, 2003), the latter providing a model to study the mechanism(s) involved.…”

Section: Introductionmentioning

confidence: 99%

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Serine/threonine protein kinase SGK1 in glucocorticoid-dependent transdifferentiation of pancreatic acinar cells to hepatocytes

Wallace

Long

Fairhall

et al. 2011

Journal of Cell Science

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Elevated glucocorticoid levels result in the transdifferentiation of pancreatic acinar cells into hepatocytes through a process that requires a transient repression of WNT signalling upstream of the induction of C/EBP-β. However, the mechanism by which glucocorticoid interacts with WNT signalling is unknown. A screen of microarray data showed that the serine/threonine protein kinase SGK1 (serum- and glucocorticoid-regulated kinase 1) was markedly induced in the model B-13 pancreatic rat acinar cell line after glucocorticoid treatment (which converts them into hepatocyte-like ‘B-13/H’ cells) and this was confirmed at the level of mRNA (notably an alternatively transcribed SGK1C form) and protein. Knockdown of SGK1 using an siRNA designed to target all variant transcripts inhibited glucocorticoid-dependent transdifferentiation, whereas overexpression of the human C isoform (and also the human SGK1F isoform, for which no orthologue in the rat has been identified) alone – but not the wild-type A form – inhibited distal WNT signalling Tcf/Lef transcription factor activity, and converted B-13 cells into B-13/H cells. These effects were lost when the kinase functions of SGK1C and SGK1F were mutated. Inhibition of SGK1 kinase activity also inhibited glucocorticoid-dependent transdifferentiation. Expression of SGK1C and SGK1F resulted in the appearance of phosphorylated β-catenin, and recombinant SGK1 was shown to directly phosphorylate purified β-catenin in vitro in an ATP-dependent reaction. These data therefore demonstrate a crucial role for SGK1 induction in B-13 cell transdifferentiation to B-13/H hepatocytes and suggest that direct phosphorylation of β-catenin by SGK1C represents the mechanism of crosstalk between glucocorticoid and WNT signalling pathways.

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“…Interestingly, CRH-Tg mice have large increases in adipose triglyceride futile cycling with increased rate of both lipolysis and reesterifi cation [ 82 ]. CRH-Tg mice display age-dependent malabsorption that is due to a "transdifferentiation" of exocrine pancreas to express hepatocyte markers [ 83 ].…”

Section: Non-gr Mutants Relevant To Glucocorticoid Signalingmentioning

confidence: 99%

Animal Models of Altered Glucocorticoid Signaling

Harris

2015

Advances in Experimental Medicine and Biology

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In this chapter we will review genetically engineered mice with alterations in glucocorticoid signaling. Most of the mice involve direct alterations to the glucocorticoid receptor locus, but we will touch briefly on other relevant models including 11-β-HSD transgenics which alter tissue levels of ligand as well as mice with glucocorticoid excess. Of course, the number of mice with mutations in genes such as GR targets and transcriptional coregulators is beyond the scope of this chapter.

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Disrupted Pancreatic Exocrine Differentiation and Malabsorption in Response to Chronic Elevated Systemic Glucocorticoid

Cited by 20 publications

References 25 publications

Glucocorticoid-dependent transdifferentiation of pancreatic progenitor cells into hepatocytes is dependent on transient suppression of WNT signalling

Glucocorticoid-dependent transdifferentiation of pancreatic progenitor cells into hepatocytes is dependent on transient suppression of WNT signalling

Serine/threonine protein kinase SGK1 in glucocorticoid-dependent transdifferentiation of pancreatic acinar cells to hepatocytes

Animal Models of Altered Glucocorticoid Signaling

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