scholarly journals The roles of glucagon-like peptide-2 and the intestinal epithelial insulin-like growth factor-1 receptor in regulating microvillus length

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Melanie A. Markovic ◽  
Patricia L. Brubaker
Keyword(s):  
Growth Factor ◽  
Brush Border ◽  
Brush Border Membrane ◽  
Jejunal Mucosa ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Intestinal Epithelial ◽  
Glucagon Like Peptide ◽  
Long Acting ◽  
Downstream Mediator

Abstract Microvilli are tiny projections on the apical end of enterocytes, aiding in the digestion and absorption of nutrients. One of their key features is uniform length, but how this is regulated is poorly understood. Glucagon-like peptide-2 (GLP-2) has been shown to increase microvillus length but, the requirement of its downstream mediator, the intestinal epithelial insulin-like growth factor-1 receptor (IE-IGF-1R), and the microvillus proteins acted upon by GLP-2, remain unknown. Using IE-IGF-1R knockout (KO) mice, treated with either long-acting human (h) (GLY2)GLP-2 or vehicle for 11d, it was found that the h(GLY2)GLP-2-induced increase in microvillus length required the IE-IGF-1R. Furthermore, IE-IGF-1R KO alone resulted in a significant decrease in microvillus length. Examination of the brush border membrane proteome as well as of whole jejunal mucosa demonstrated that villin was increased with h(GLY2)GLP-2 treatment in an IE-IGF-1R-dependent manner. Under both basal conditions and with h(GLY2)GLP-2 treatment of the IE-IGF-1R KO mice, changes in villin, IRTKS-1, harmonin, β-actin, and myosin-1a did not explain the decrease in microvillus length, in either the brush border or jejunal mucosa of KO animals. Collectively, these studies define a new role for the IE-IGF-1R within the microvillus, in both the signaling cascade induced by GLP-2, as well as endogenously.

scholarly journals The Intestinal Epithelial Insulin-Like Growth Factor-1 Receptor Links Glucagon-Like Peptide-2 Action to Gut Barrier Function

Endocrinology ◽  
2014 ◽  
Vol 155 (2) ◽  
pp. 370-379 ◽  
Author(s):  
Charlotte X. Dong ◽  
Wen Zhao ◽  
Chloe Solomon ◽  
Katherine J. Rowland ◽  
Cameron Ackerley ◽  
...  
Keyword(s):  
Growth Factor ◽  
Barrier Function ◽  
Insulin Like Growth Factor ◽  
Intestinal Epithelial ◽  
Gut Barrier ◽  
Gut Barrier Function ◽  
Glucagon Like Peptide

Loss of Glucagon-Like Peptide-2–Induced Proliferation Following Intestinal Epithelial Insulin-Like Growth Factor-1–Receptor Deletion

2011 ◽  
Vol 141 (6) ◽  
pp. 2166-2175.e7 ◽  
Author(s):  
Katherine J. Rowland ◽  
Shivangi Trivedi ◽  
Daiyoon Lee ◽  
Ken Wan ◽  
Rohit N. Kulkarni ◽  
...  
Keyword(s):  
Growth Factor ◽  
Insulin Like Growth Factor ◽  
Intestinal Epithelial ◽  
Glucagon Like Peptide

scholarly journals Insulin-like growth factor-binding protein-4 inhibits epithelial growth and proliferation in the rodent intestine

2018 ◽  
Vol 315 (2) ◽  
pp. G206-G219 ◽  
Author(s):  
Kaori Austin ◽  
Derek Tsang ◽  
Jennifer A. Chalmers ◽  
Michael F. Maalouf ◽  
Patricia L. Brubaker
Keyword(s):  
Growth Factor ◽  
Binding Protein ◽  
Dependent Manner ◽  
Insulin Like Growth Factor ◽  
Intestinal Epithelial ◽  
Ki 67 ◽  
Factor Binding ◽  
Gut Hormone ◽  
And Control ◽  
Epithelial Growth

Insulin-like growth factor-binding protein-4 (IGFBP-4) is a binding protein that modulates the action of insulin-like growth factor-1 (IGF-1), a growth factor whose presence is required for the intestinotrophic effects of glucagon-like peptide-2 (GLP-2). GLP-2 is a gut hormone that uses both IGF-1 and epidermal growth factor (EGF) as intermediary factors to promote intestinal growth. Therefore, to elucidate the mechanism through which IGFBP-4 regulates IGF-1 activity in the intestine, proliferation assays were conducted using rat intestinal epithelial cells (IEC-6). IGF-1 and EGF synergistically enhanced proliferation, an effect that was dose-dependently decreased by IGFBP-4 ( P < 0.05–0.001) in an IGF-1 receptor (R)- and MEK1/2- but not a phosphatidylinositol 3-kinase-dependent manner ( P > 0.05 for IGFBP-4 effects with IGF-1R and MEK1/2 inhibitors). Intestinal organoids derived from IGFBP-4 knockout mice demonstrated significantly greater Ki-67 expression and an enhanced surface area increase in response to IGF-1 treatment, compared with organoids from control mice ( P < 0.05–0.01). GLP-2 is also known to increase the mucosal expression of IGFBP-4 mRNA. To investigate whether this occurs through the actions of its intermediaries, IGF-1 and EGF, inducible intestinal epithelial-IGF-1R knockout and control mice were treated for 10 days with and without the pan-ErbB inhibitor, CI-1033. However, no differences in mucosal IGFBP-4 mRNA expression were found for any of the treatment groups ( P > 0.05). Consistently, IEC-6 cells treated with IGF-1 and/or EGF displayed no alteration in IGFBP-4 mRNA or in cellular and secreted IGFBP-4 protein ( P > 0.05). Overall, this study establishes that endogenous IGFBP-4 plays an important role in inhibiting IGF-1-induced intestinal epithelial proliferation and that mucosal IGFBP-4 expression is independent of IGF-1 and EGF. NEW & NOTEWORTHY This study demonstrates, for the first time, the inhibitory role of locally expressed insulin-like growth factor-binding protein-4 (IGFBP-4) on the intestinal proliferative actions of IGF-1 and supports the notion of the synergistic roles of IGF-1 and EGF in promoting intestinal epithelial growth. In turn, intestinal IGFBP-4 expression was not found to be regulated by IGF-1 and/or EGF.

scholarly journals Functional coupling of the downregulated in adenoma Cl−/base exchanger DRA and the apical Na+/H+ exchangers NHE2 and NHE3

2009 ◽  
Vol 296 (2) ◽  
pp. G202-G210 ◽  
Author(s):  
Mark W. Musch ◽  
Donna L. Arvans ◽  
Gary D. Wu ◽  
Eugene B. Chang
Keyword(s):  
Carbonic Anhydrase ◽  
Brush Border ◽  
Brush Border Membrane ◽  
Intestinal Epithelial Cells ◽  
Functional Coupling ◽  
Intestinal Epithelial ◽  
Colon Cells ◽  
Base Exchange ◽  
Synaptotagmin I

Non-nutrient-dependent salt absorption across the brush-border membrane of intestinal epithelial cells is primarily mediated by coupled apical Na+/H+ (aNHE) and anion exchange transport, with the latter suspected of being mediated by DRA (downregulated in adenoma; SLC26A3) that is defective in congenital chloridorrhea. To investigate DRA in greater detail and determine whether DRA and NHE activities can be coupled, we measured 22Na+ and 36Cl− uptake in Caco2BBE colon cells infected with the tet-off-inducible DRA transgene. Under basal conditions, DRA activity was low in normal and infected Caco2BBE cells in the presence of tetracycline, whereas NHE activities could be easily detected. When apical NHE activity was increased by transfection or serum-induced expression of the aNHE isoforms NHE2 and NHE3, increased 36Cl− uptake was observed. Inhibition of DRA activity by niflumic acid was greater than that by DIDS as well as by the NHE inhibitor dimethylamiloride and the carbonic anhydrase inhibitor methazolamide. DRA activity was largely aNHE-dependent, whereas a component of DRA-independent aNHE uptake continued to be observed. Coupled aNHE and DRA activities were inhibited by increased cellular cAMP and calcium and were associated with synaptotagmin I-dependent, clathrin-mediated endocytosis. In summary, these data support the role of DRA in electroneutral NaCl absorption involving functional coupling of Cl−/base exchange and apical NHE.

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