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ABSTRACT Background High intakes of fructose are associated with metabolic diseases, including hypertriglyceridemia and intestinal tumor growth. Although small intestinal epithelia consist of many different cell types, express lipogenic genes, and convert dietary fructose to fatty acids, there is no information on the identity of the cell type(s) mediating this conversion and on the effects of fructose on lipogenic gene expression. Objectives We hypothesized that fructose regulates the intestinal expression of genes involved in lipid and apolipoprotein synthesis, that regulation depends on the fructose transporter solute carrier family 2 member a5 [Slc2a5 (glucose transporter 5)] and on ketohexokinase (Khk), and that regulation occurs only in enterocytes. Methods We compared lipogenic gene expression among different organs from wild-type adult male C57BL mice consuming a standard vivarium nonpurified diet. We then gavaged twice daily for 2.5 d fructose or glucose solutions (15%, 0.3 mL per mouse) into wild-type, Slc2a5-knockout (KO), and Khk-KO mice with free access to the nonpurified diet and determined expression of representative lipogenic genes. Finally, from mice fed the nonpurified diet, we made organoids highly enriched in enterocyte, goblet, Paneth, or stem cells and then incubated them overnight in 10 mM fructose or glucose. Results Most lipogenic genes were significantly expressed in the intestine relative to the kidney, liver, lung, and skeletal muscle. In vivo expression of Srebf1, Acaca, Fasn, Scd1, Dgat1, Gk, Apoa4, and Apob mRNA and of Scd1 protein increased (P < 0.05) by 3- to 20-fold in wild-type, but not in Slc2a5-KO and Khk-KO, mice gavaged with fructose. In vitro, Slc2a5- and Khk-dependent, fructose-induced increases, which ranged from 1.5- to 4-fold (P < 0.05), in mRNA concentrations of all these genes were observed only in organoids enriched in enterocytes. Conclusions Fructose specifically stimulates expression of mouse small intestinal genes for lipid and apolipoprotein synthesis. Secretory and stem cells seem incapable of transport- and metabolism-dependent lipogenesis, occurring only in absorptive enterocytes.
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Comparative Effects of Allulose, Fructose, and Glucose on the Small Intestine
Despite numerous studies on the health benefits of the rare sugar allulose, its effects on intestinal mucosal morphology and function are unclear. We therefore first determined its acute effects on the small intestinal transcriptome using DNA microarray analysis following intestinal allulose, fructose and glucose perfusion in rats. Expression levels of about 8-fold more genes were altered by allulose compared to fructose and glucose perfusion, suggesting a much greater impact on the intestinal transcriptome. Subsequent pathway analysis indicated that nutrient transport, metabolism, and digestive system development were markedly upregulated, suggesting allulose may acutely stimulate these functions. We then evaluated whether allulose can restore rat small intestinal structure and function when ingested orally following total parenteral nutrition (TPN). We also monitored allulose effects on blood levels of glucagon-like peptides (GLP) 1 and 2 in TPN rats and normal mice. Expression levels of fatty acid binding and gut barrier proteins were reduced by TPN but rescued by allulose ingestion, and paralleled GLP-2 secretion potentially acting as the mechanism mediating the rescue effect. Thus, allulose can potentially enhance disrupted gut mucosal barriers as it can more extensively modulate the intestinal transcriptome relative to glucose and fructose considered risk factors of metabolic disease.
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- Award ID(s):
- 1754783
- PAR ID:
- 10409773
- Date Published:
- Journal Name:
- Nutrients
- Volume:
- 14
- Issue:
- 15
- ISSN:
- 2072-6643
- Page Range / eLocation ID:
- 3230
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/nu14153230
