Fructose is now such an important component of human diets that increasing attention is being focused on the fructose transporter GLUT5. In this review, we describe the regulation of GLUT5 not only in the intestine and testis, where it was first discovered, but also in the kidney, skeletal muscle, fat tissue, and brain where increasing numbers of cell types have been found to have GLUT5. GLUT5 expression levels and fructose uptake rates are also significantly affected by diabetes, hypertension, obesity, and inflammation and seem to be induced during carcinogenesis, particularly in the mammary glands. We end by highlighting research areas that should yield information needed to better understand the role of GLUT5 during normal development, metabolic disturbances, and cancer.

Fructose intake has increased dramatically since humans were hunter-gatherers, probably outpacing the capacity of human evolution to make physiologically healthy adaptations. Epidemiological data indicate that this increasing trend continued until recently. Excessive intakes that chronically increase portal and peripheral blood fructose concentrations to >1 and 0.1 mM, respectively, are now associated with numerous diseases and syndromes. The role of the fructose transporters GLUT5 and GLUT2 in causing, contributing to or exacerbating these diseases is not well known. GLUT5 expression seems extremely low in neonatal intestines, and limited absorptive capacities for fructose may explain the high incidence of malabsorption in infants and cause problems in adults unable to upregulate GLUT5 levels to match fructose concentrations in the diet. GLUT5-and GLUT2-mediated fructose effects on intestinal electrolyte transporters, hepatic uric acid metabolism, as well as renal and cardiomyocyte function, may play a role in fructose-induced hypertension. Likewise, GLUT2 may contribute to the development of non-alcoholic fatty liver disease by facilitating the uptake of fructose. Finally, GLUT5 may play a role in the atypical growth of certain cancers and fat tissues. We also highlight research areas that should yield information needed to better understand the role of these GLUTs in fructose-induced diseases. Abbreviations GCMS, gas chromatography mass spectrometry; GLUT, glucose transporter protein; HPLC, high-performance liquid chromatography; KHK, ketohexokinase or fructokinase; NAFLD, non-alcoholic fatty liver disease; PAT1, chloride-anion exchanger; SGLT1, sodium-dependent glucose transporter 1;

The constant self renewal and differentiation of adult intestinal stem cells maintains a functional intestinal mucosa for a lifetime. However, the molecular mechanisms that regulate intestinal stem cell division and epithelial homeostasis are largely undefined. We report here that the small GTPases Cdc42 and Rab8a are critical regulators of these processes in mice. Conditional ablation of Cdc42 in the mouse intestinal epithelium resulted in the formation of large intracellular vacuolar structures containing microvilli (microvillus inclusion bodies) in epithelial enterocytes, a phenotype reminiscent of human microvillus inclusion disease (MVID), a devastating congenital intestinal disorder that results in severe nutrient deprivation. Further analysis revealed that Cdc42-deficient stem cells had cell division defects, reduced capacity for clonal expansion and differentiation into Paneth cells, and increased apoptosis. Cdc42 deficiency impaired Rab8a activation and its association with multiple effectors, and prevented trafficking of Rab8a vesicles to the midbody. This impeded cytokinesis, triggering crypt apoptosis and disrupting epithelial morphogenesis. Rab8a was also required for Cdc42-GTP activity in the intestinal epithelium, where continued cell division takes place. Furthermore, mice haploinsufficient for both Cdc42 and Rab8a in the intestine demonstrated abnormal crypt morphogenesis and epithelial transporter physiology, further supporting their functional interaction. These data suggest that defects of the stem cell niche can cause MVID. This hypothesis represents a conceptual departure from the conventional view of this disease, which has focused on the affected enterocytes, and suggests stem cell-based approaches could be beneficial to infants with this often lethal condition.

Paneth cells are the primary source of C-type lysozyme, a b-1,4-N-acetylmuramoylhydrolase that enzymatically processes bacterial cell walls. Paneth cells are normally present in human cecum and ascending colon, but are rarely found in descending colon and rectum; Paneth cell metaplasia in this region and aberrant lysozyme production are hallmarks of inflammatory bowel disease (IBD) pathology. Here, we examined the impact of aberrant lysozyme production in colonic inflammation. Targeted disruption of Paneth cell lysozyme (Lyz1) protected mice from experimental colitis. Lyz1-deficiency diminished intestinal immune responses to bacterial molecular patterns and resulted in the expansion of lysozyme-sensitive mucolytic bacteria, including Ruminococcus gnavus, a Crohn's disease-associated pathobiont. Ectopic lysozyme production in colonic epithelium suppressed lysozyme-sensitive bacteria and exacerbated colitis. Transfer of R. gnavus into Lyz1 À/À hosts elicited a type 2 immune response, causing epithelial reprograming and enhanced anti-colitogenic capacity. In contrast, in lysozyme-intact hosts, processed R. gnavus drove pro-inflammatory responses. Thus, Paneth cell lysozyme balances intestinal anti-and pro-inflammatory responses, with implications for IBD.