Biology subjects

Aydemir, T. B.

Publications and source records attributed to Aydemir, T. B..

6 recordsLinked to original sources

bioRxiv2026

Hepatic stearoyl-CoA desaturase-1 is specifically suppressed by dextran sodium sulfate but does not influence colitis sensitivity

The delta-9 desaturase stearoyl-CoA desaturase-1 (SCD1) catalyzes the conversion of saturated fatty acids to monounsaturated fatty acids (MUFA) and is highly expressed in liver and adipocytes. Previous studies have demonstrated that treating mice with dextran sulfate sodium (DSS), a chemical inducer of ulcerative colitis, results in severe downregulation of SCD1 in the liver. However, the specific role of hepatic SCD1 in modulating colitis severity, as well as the impact of DSS on SCD1 and other lipogenic factors in other tissues has not been investigated. Here we show that downregulation of hepatic SCD1 following DSS treatment is not accompanied by changes to other lipogenic genes in the liver. In contrast, adipose tissue demonstrates coordinated reductions in lipogenic genes, including SCD1 and SCD2, while the colon does not display any perturbation of these targets. Furthermore, we demonstrate that the downregulation of hepatic SCD1 occurs independently of sterol regulatory element binding protein-1c (SREBP-1c) and does not require an intact gut microbiome. Interestingly, a distinct model of colitis induced by IL-10 deficiency does not result in downregulation of hepatic SCD1. Concomitant with transcriptional changes, DSS treatment is associated with significant remodeling of the hepatic lipidome, including reductions in total phospholipids (PLs) and reduced MUFA-containing PLs and triacyglycerols (TAGs), consistent with the observed reduction in SCD1. Interestingly, hepatic cholesterol esters and plasma lipids including free cholesterol and glycerophospholipids were significantly elevated following DSS treatment. Given the significant reduction in hepatic SCD1 following DSS treatment, we tested a role for liver SCD1 in modulating colitis sensitivity. Mice with a targeted deletion of hepatic SCD1 were not more prone to colitis, indicating that the loss of hepatic SCD1, while a consequence of DSS-induced colitis, does not mediate colitis sensitivity in vivo. SynopsisHepatic SCD1 does not modulate colitis severity upon DSS exposure. However, DSS-induced colitis elicits significant lipid metabolism dysfunction, demonstrated by elevated plasma and liver lipids, particularly plasma cholesterol and hepatic cholesterol esters, highlighting a role for gutliver crosstalk following colonic inflammation.

physiology↗

bioRxiv2025

Multiomics Approach to Regionally Profile Zinc-Driven Host-Gut Microbiome Interactions in the Intestinal Tract

Zinc deficiency (ZnD) is a major risk factor for metabolic and inflammatory diseases associated with gut microbial alterations, such as obesity, type 2 diabetes, and inflammatory bowel disease. Despite its importance, there are no established dietary recommendations for zinc supplementation in individuals with these conditions, except in cases of severe diarrhea in children. This gap stems from inconsistent outcomes in zinc supplementation trials, suggesting an incomplete understanding of zinc-mediated spatial and temporal regulation within the host-microbiome interface. This study employed a multiomics approach to investigate zinc-driven host-gut microbial interactions in the intestinal tract of mice fed zinc-adequate or ZnD diets. Radio tracing and metallomics analyses uncovered differential zinc abundance across intestinal tissues, with conventionalized germ-free mice displaying significantly lower zinc levels than germ-free mice, highlighting the reciprocal regulation of zinc between host tissues and gut microbes. Transcriptomic analyses revealed region-specific effects of ZnD, including altered energy metabolism and apoptosis in the small intestine, and impaired barrier function and redox processes in the colon. Metagenomics profiling revealed that ZnD reduced microbial diversity in the small intestine, while the cecum and colon were protected from diversity loss but exhibited an increased abundance of pathogenic bacteria. Correlation analyses linked tissue-specific host gene expression to shifts in microbial populations, identifying potential microbial mediators of host transcription changes under ZnD. Collectively, these findings emphasize the critical role of zinc in spatially regulating host-microbiome interactions, advancing our understanding of region-specific impacts of ZnD on the GI tract and disease risk. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/662895v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@235941org.highwire.dtl.DTLVardef@b8f1deorg.highwire.dtl.DTLVardef@f283eorg.highwire.dtl.DTLVardef@11b039a_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

The Ins and Outs of Manganese: ZIP14 facilitates the efflux of excess manganese from the brain.

Manganese (Mn) is essential for many enzymatic processes in the brain; however, Mn overload can lead to neurotoxicity and behavioral deficits. The blood-brain barrier (BBB), comprised of polarized endothelial cells, tightly regulates metals in and out of the brain. ZIP14 (SLC39A14) is a metal transporter more recently found to transport Mn, with mutations in human SLC39A14 resulting in brain Mn accumulation and neurological deficits. However, ZIP14s precise localization and role in BBB endothelial cells remain unclear. Here, we show in vivo ZIP14 expression in BBB endothelial cells, which upregulates following Mn supplementation. Using expansion microscopy, we observed a shift in ZIP14 localization from an equal apical-basolateral distribution to predominantly basolateral after Mn exposure. Endothelial-specific Zip14 KO (EKO) mice exhibited impaired Mn efflux from the brain and increased brain Mn accumulation after nasal delivery and dietary Mn supplementation. In vitro studies using primary endothelial cells from EKO mice and ZIP14-overexpressing hCMEC/D3 cells confirmed that ZIP14 primarily mediates basolateral-to-apical Mn transport. Collectively, our results demonstrate that ZIP14 is critical for brain Mn clearance, highlighting its potential as a therapeutic target to mitigate Mn-induced neurotoxicity. Significance StatementOur study reveals that the endothelial metal transporter ZIP14 plays a critical role in removing excess Mn from the brain. Using expansion microscopy, genetic manipulation, metallomics, and transport studies employing radiolabeled Mn, we demonstrate that ZIP14 undergoes strategic relocalization in response to Mn exposure and primarily functions in basolateral-to-apical transport. Deletion of endothelial ZIP14 leads to brain Mn accumulation, establishing its fundamental role in protecting against Mn-induced neurotoxicity. This finding provides mechanistic insight into how the brain protects itself against Mn overload and why ZIP14 mutations in humans result in brain Mn accumulation.

physiology↗

bioRxiv2021

Metal transporter SLC39A14/ZIP14 modulates regulation between the gut microbiome and host metabolism

Zinc (Zn) plays a critical role in maintaining intestinal homeostasis by regulating intestinal epithelial cells, host immune cells, and gut microbiome community composition. Deletion of metal transporter Slc39a14/Zip14 causes spontaneous intestinal permeability with low-grade chronic inflammation, mild hyperinsulinemia, and greater body fat with insulin resistance in adipose, suggesting a role for ZIP14-mediated intestinal metal transport in regulating both intestinal homeostasis and systemic metabolism. Here, we showed the function of ZIP14-mediated Zn transport in the gut microbiome composition and how ZIP14-linked changes to gut microbiome community composition are correlated with changes in host metabolism. Deletion of Zip14 generated Zn-deficient epithelial cells and luminal content in the entire intestinal tract; reduced bacterial diversity and Saccharomyces cerevisiae (S. cerevisiae) overgrowth; altered host metabolome; and shifted host energy metabolism toward glucose utilization. This work provides evidence for the regulation of gut microbiome composition, host metabolome, and energy metabolism by metal transporter ZIP14. SignificanceIntestinal permeability, gut dysbiosis, and Zn dyshomeostasis are emerging signatures of inflammatory bowel diseases and metabolic disorders such as type-2-diabetes and obesity. Zn deficiency is a common clinical finding among these diseases. Zn is essential for the regulation of the intestinal epithelial cells, host immune cells, and the gut microbiome. Transporter-mediated mobilization of Zn plays a critical role in maintaining intestinal homeostasis by facilitating the targeted tissue/cell-specific function. However, studies are lacking in linking transporter-mediated Zn mobilization, gut microbiome, hosts intestinal health, and metabolism. Using the systems-level approach, this study revealed novel findings that deletion of Slc39a14/Zip14 resulted in altered intestinal Zn homeostasis, gut microbiome composition, host metabolome and energy metabolism.

physiology↗

bioRxiv2020

Intestine-specific deletion of metal transporter Zip14 (Slc39a14) causes brain manganese overload and locomotor defects of manganism

Impaired manganese (Mn) homeostasis can result in excess Mn accumulation in specific brain regions and neuropathology. Maintaining Mn homeostasis and detoxification is dependent on effective Mn elimination. Specific metal transporters control Mn homeostasis. Human carriers of mutations in the metal transporter ZIP14 and whole-body Zip14 KO (WB-KO) mice display similar phenotypes, including spontaneous systemic and brain Mn overload, and motor dysfunction. Initially, it was believed that Mn accumulation due to ZIP14 mutations caused by impaired hepatobiliary Mn elimination. However, liver-specific Zip14 KO mice (L-KO) did not show systemic Mn accumulation or motor deficits. ZIP14 is highly expressed in the small intestine and is localized to the basolateral surface of enterocytes. Thus we hypothesized that basolaterally-localized ZIP14 in enterocytes provides another route for elimination of Mn. Using wild type and intestine-specific ZIP14 KO (I-KO) mice, we have shown that ablation of intestinal Zip14 is sufficient to cause systemic and brain Mn accumulation. The lack of intestinal ZIP14- mediated Mn excretion was compensated for by the hepatobiliary system; however, it was not sufficient to maintain Mn homeostasis. When supplemented with extra dietary Mn, I-KO mice displayed some motor dysfunctions, brain Mn accumulation based on both MRI imaging and chemical analysis, thus demonstrating the importance of intestinal ZIP14 as a route of Mn excretion. A defect in intestinal Zip14 expresssion likely could contribute to the Parkinson-like Mn accumulation of manganism. New & NoteworthyMn-induced parkinsonism is recognized as rising in frequency due to both environmental factors and genetic vulnerability, yet currently, there is no cure. We provide evidence in an integrative animal model that basolaterally localized ZIP14 regulates Mn excretion and detoxification and that deletion of intestinal ZIP14 leads to systemic and brain Mn accumulation, providing robust evidence for the indispensable role of intestinal ZIP14 on Mn excretion.

neuroscience↗

bioRxiv2019

Mechanism of manganese dysregulation of dopamine neuronal activity

Manganese exposure produces Parkinsons-like neurological symptoms, suggesting a selective dysregulation of dopamine transmission. It is unknown, however, how manganese accumulates in dopaminergic brain regions or how it regulates the activity of dopamine neurons. Our in vivo studies suggest manganese accumulates in dopamine neurons of the ventral tegmental area and substantia nigra via nifedipine-sensitive Ca2+ channels. Manganese produces a Ca2+ channel-mediated current which increases neurotransmitter release and rhythmic firing activity of dopamine neurons. These increases are prevented by blockade of Ca2+ channels and depend on downstream recruitment of Ca2+-activated potassium channels to the plasma membrane. These findings demonstrate the mechanism of manganese-induced dysfunction of dopamine neurons, and reveal a potential therapeutic target to attenuate manganese-induced impairment of dopamine transmission.\n\nSignificance StatementManganese is a trace element critical to many physiological processes. Overexposure to manganese is an environmental risk factor for neurological disorders such as a Parkinsons disease-like syndrome known as manganism. We found manganese dose-dependently increased the excitability of dopamine neurons, decreased the amplitude of action potentials, and narrowed action potential width. Blockade of Ca2+ channels prevented these effects as well as manganese accumulation in the mouse midbrain in vivo. Our data provide a potential mechanism for manganese-regulation of dopaminergic neurons.

cell biology↗