Biology subjects

Sunuwar, L.

Publications and source records attributed to Sunuwar, L..

3 recordsLinked to original sources

bioRxiv2025

Differential Regulation of NHE3 Expression in Type 1 and Type 2 Diabetic Intestine: Impaired Endosomal Regulation of NHE3 Expression in Type 1 Diabetes

Chronic diarrhea is a frequent gastrointestinal complication in both type 1 (T1D) and type 2 diabetes (T2D), though the underlying mechanisms differ: T1D is linked to autonomic neuropathy and disrupted transporter regulation, while T2D is often linked to medications and intestinal inflammation. Using streptozotocin-induced mouse models of T1D and T2D, we observed increased luminal fluid in the small intestine of both. Given the role of Na+/H+ exchanger 3 (NHE3) in fluid absorption and its loss in most diarrheal diseases, we examined NHE3 expression across intestinal segments. In T1D, NHE3 protein was significantly reduced in the duodenum and jejunum without changes in mRNA, suggesting post-transcriptional regulation. In contrast, T2D mice exhibited reduced NHE3 protein and mRNA, restricted to the proximal colon. To investigate mechanisms underlying NHE3 loss in T1D, we evaluated endosomal scaffolding proteins involved in NHE3 trafficking. While our previous work showed that the Sorting Nexin-27 (SNX27)-retromer complex does not regulate NHE3 protein stability, we found that SNX17 was significantly decreased in the small intestine of T1D mice but unchanged in T2D. SNX17 knockdown in SK-CO15 cells reduced NHE3 activity and stability. A GST pull-down assay showed that SNX17 interacts with the C-terminus of NHE3. Mutation of the NHE3 distal NPxY motif disrupted this interaction, leading to reduced NHE3 expression and increased degradation. These findings reveal segment-specific and mechanistically distinct causes of diabetic diarrhea in T1D versus T2D, and identify SNX17 loss as a contributor to reduced NHE3 stability and activity in T1D, likely promoting diabetic diarrhea. New and NoteworthyThis study identifies distinct mechanisms of impaired sodium absorption contributing to diabetic diarrhea in type-1 and type-2 diabetes. We identify SNX17 as a novel regulator of NHE3 in the small intestine, showing that SNX17 loss in T1D contributes to post-translational NHE3 destabilization. In contrast, T2D-associated NHE3 downregulation is transcriptional and confined to the colon. These findings reveal disease- and region-specific regulatory pathways that drive impaired fluid absorption in diabetes, with direct implications for the development of targeted therapies. Graphical abstract Schematic overview of differential NHE3 regulation in diabetic diarrhea.In Type 1 Diabetes (T1D), reduced SNX17 expression in the small intestine causes increased degradation of NHE3 and impaired sodium absorption. In Type 2 Diabetes (T2D), SNX17 levels remain unchanged in the small intestine, but NHE3 expression is transcriptionally downregulated in the proximal colon. These distinct mechanisms contribute to segment-specific differential regulation of NHE3 in T1 and T2D diabetes. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=101 SRC="FIGDIR/small/675364v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@eabf0aorg.highwire.dtl.DTLVardef@1a46891org.highwire.dtl.DTLVardef@cd2d5corg.highwire.dtl.DTLVardef@5d185b_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2023

Hepatobiliary manganese homeostasis is dynamic in the setting of illness in mice

Manganese is a diet-derived micronutrient that is essential for critical cellular processes like redox homeostasis, protein glycosylation, and lipid and carbohydrate metabolism. Control of Mn availability, especially at the local site of infection, is a key component of the innate immune response. Less has been elucidated about Mn homeostasis at the systemic level. In this work, we demonstrate that systemic Mn homeostasis is dynamic in response to illness in mice. This phenomenon is evidenced in male and female mice, mice of two genetic backgrounds (C57/BL6 and BALB/c), in multiple models of acute (dextran-sodium sulfate-induced) and chronic (enterotoxigenic Bacteriodes fragilis) colitis, and systemic infection with Candida albicans. When mice were fed a standard corn-based chow with excess Mn (100 ppm), liver Mn decreased and biliary Mn increased 3-fold in response to infection or colitis. Liver iron, copper, and zinc were unchanged. When dietary Mn was restricted to minimally adequate amounts (10ppm), baseline hepatic Mn levels decreased by approximately 60% in the liver, and upon induction of colitis, liver Mn did not decrease further, however biliary Mn still increased 20-fold. In response to acute colitis, hepatic Slc39a8 mRNA (gene encoding the Mn importer, Zip8) and Slc30a10 mRNA (gene encoding the Mn exporter, Znt10) are decreased. Zip8 protein is decreased. Illness- associated dynamic Mn homeostasis may represent a novel host immune/inflammatory response that reorganizes systemic Mn availability through differential expression of key Mn transporters with down-regulation of Zip8. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/533688v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@a1db9aorg.highwire.dtl.DTLVardef@588af9org.highwire.dtl.DTLVardef@10be4b0org.highwire.dtl.DTLVardef@1d2eebc_HPS_FORMAT_FIGEXP M_FIG C_FIG Created with BioRender.com

physiology↗

bioRxiv2019

Organoid-derived Duodenum Intestine-Chip for preclinical drug assessment in a human relevant system

Induction of intestinal drug metabolizing enzymes can complicate the development of new drugs, owing to potential to cause drug-drug interactions (DDIs) leading to changes in pharmacokinetics, safety and efficacy. The development of a human relevant model of the adult intestine that accurately predicts CYP450 induction could help address this challenge as species differences preclude extrapolation from animals. Here, we combined organoids and Organ-Chip technology to create a human Duodenum Intestine-Chip that emulates intestinal tissue architecture and functions, that are relevant for the study of drug transport, metabolism, and DDI. Duodenum Intestine-Chip demonstrates the polarized cell architecture, intestinal barrier function, presence of specialized cell subpopulations, and in vivo-relevant expression, localization, and function of major intestinal drug transporters. Notably, in comparison to Caco-2, it displays improved CYP3A4 expression and induction capability. This model could enable improved in vitro to in vivo extrapolation for better predictions of human pharmacokinetics and risk of DDIs.

cell biology↗