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

Melanie A. Markovic,Patricia L. Brubaker

doi:10.1038/s41598-019-49510-5

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.

Highlights

The major site of nutrient digestion and absorption occurs within the enterocytes of the small intestine
The Glucagon-like peptide-2 (GLP-2) receptor is localized on enteroendocrine cells, enteric neurons, and intestinal subepithelial myofibroblasts (ISEMFs), a syncytium of cells located underneath the epithelium[18,24,25,26]
The aim of this study was to determine whether the IE-IGF-1R is required for the increase in microvillus length following GLP-2 treatment, and which brush border proteins are acted upon by GLP-2 to cause the enhancement in microvillus length

Summary

Introduction

The major site of nutrient digestion and absorption occurs within the enterocytes of the small intestine. Microvilli are tiny, finger-like projections located on the apical surface of enterocytes, and are collectively referred to as the brush border They increase the absorptive surface area by 9- to 16-fold[1], and house over 22 digestive enzymes and 53 channels and transporters[2]. Forming the entire microvillus region on the apical surface of the enterocytes requires plasma membrane bending proteins, such as insulin receptor tyrosine kinase substrate-1 (IRTKS-1)[3,4]. It has been shown that the presence of intermicrovillar links is important for maintaining uniform length[13] It is not well understood how these changes in brush border proteins are controlled. The aim of this study was to determine whether the IE-IGF-1R is required for the increase in microvillus length following GLP-2 treatment, and which brush border proteins are acted upon by GLP-2 to cause the enhancement in microvillus length

Objectives

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Conclusion