Butyrate-induced expression of proglucagon: implications for enteroendocrine signaling and intestinal growth

While the gastrointestinal tract is primarily recognized for its digestive and absorptive capacity, it is also the largest endocrine organ in the body. There are a number of different types of endocrine cells in the gut which have the ability to mediate nutrient-gene interactions. Of interest for this research is the L cell of the distal ileum and colon which expresses the proglucagon gene. Proglucagon encodes a number of important hormones, namely glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), glicentin, and oxyntomodulin and thus may impact intestinal development and dysfunction, type 2 diabetes, and obesity. Evidence suggests that fibers and short-chain fatty acids (SCFAs), particularly butyrate, are classes of nutrients capable of regulating the proglucagon gene. To examine this, we treated enteroendocrine L cells with butyrate and found increased proglucagon mRNA abundance. However, the mechanism by which butyrate affects proglucagon was less understood. Therefore, we isolated the human proglucagon gene promoter and treated with butyrate, revealing that butyrate regulates proglucagon transcription by activating the promoter. In addition, it has been suggested that butyrate may be interacting with receptors or transporters to stimulate its effects. To examine this, we silenced the SCFA receptor GPR43 and the bitter taste receptor T2R38 and revealed that butyrate no longer had the capacity to stimulate increased proglucagon abundance. Additionally, we also examined the abundance of SCFA transporters and noted increases in SLC5A8 in the ileum and MCT-1 in the colon following supplementation of fermentable fibers into the diet. Further interaction between butyrate and proglucagon was explored by infusing SCFAs and butyrate into the lumen of the ileum and colon. The greatest effects were noted in aspects of intestinal structure, with changes noted in crypt-villus architecture, DNA, RNA, and protein concentrations throughout the intestine. These improved structural parameters corresponded with increased proglucagon abundance, suggesting GLP-2 was likely mediating these adaptations to the nutrient. Thus, the provision of the SCFA butyrate may be particularly important and beneficial to patients suffering with intestinal dysfunction, type 2 diabetes, and obesity by upregulating proglucagon expression and ultimately stimulating greater hormone release.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Nutritional Sciences

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2010

Author dc:creator

• Woodard, Jennifer Nicole

Contributors dc:contributor

• Tappenden, Kelly A.
• Garrow, Timothy A.
• Swanson, Kelly S.
• Miller, Michael J.

• intestine
• proglucagon
• butyrate
• short-chain fatty acids
• Adaptation

Statement dc:rights

• Copyright 2010 Jennifer Nicole Woodard

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/16529

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/16529