A5078807649- Trace Elements in Health
- Pancreatic function and diabetes
- Heavy Metal Exposure and Toxicity
- Iron Metabolism and Disorders
- Connective tissue disorders research
- Autophagy in Disease and Therapy
- RNA regulation and disease
- Diabetes and associated disorders
- Neurogenetic and Muscular Disorders Research
- Nuclear Structure and Function
- Folate and B Vitamins Research
- Adipose Tissue and Metabolism
- Diabetes Treatment and Management
- Adipokines, Inflammation, and Metabolic Diseases
- Diabetes Management and Research
- MicroRNA in disease regulation
- Selenium in Biological Systems
- Medical Imaging Techniques and Applications
- Alkaline Phosphatase Research Studies
- Calcium signaling and nucleotide metabolism
- RNA Research and Splicing
- FOXO transcription factor regulation
- Lipid metabolism and biosynthesis
- Whipple's Disease and Interleukins
- Neuropeptides and Animal Physiology
Gunma University
2017-2024
Institute of Developmental Physiology
2019
Juntendo University
2014-2017
Japan Agency for Medical Research and Development
2017
Kyoto University
2002-2016
Centre for Research in Engineering Surface Technology
2014
RIKEN Center for Computational Science
2011-2013
Recent genome-wide association studies demonstrated that common variants of solute carrier family 30 member 8 gene (SLC30A8) increase susceptibility to type 2 diabetes. SLC30A8 encodes zinc transporter-8 (ZnT8), which delivers ion from the cytoplasm into insulin granules. Although it is well known granules contain high amounts zinc, physiological role secreted remains elusive. In this study, we generated mice with β cell-specific Slc30a8 deficiency (ZnT8KO mice) and an unexpected functional...
Pancreatic islets in patients with type 2 diabetes mellitus (T2DM) are characterized by loss of β cells and formation amyloid deposits derived from islet polypeptide (IAPP). Here we demonstrated that treatment INS-1 human IAPP (hIAPP) enhances cell death, inhibits cytoproliferation, increases autophagosome formation. Furthermore, inhibition autophagy increased the vulnerability to cytotoxic effects hIAPP. Based on these vitro findings, examined pathogenic role hIAPP its relation...
The Aft1 transcription factor regulates the iron regulon in response to availability Saccharomyces cerevisiae. activates a battery of genes required for uptake under iron-starved conditions, whereas function is inactivated iron-replete conditions. Previously, we have shown that iron-regulated DNA binding by responsible controlled expression target genes. Here show this not due change total level or alteration activity. Rather, nuclear localization responds status, leading We identified...
The majority of CDF/ZnT zinc transporters form homo-oligomers. However, ZnT5, ZnT6, and their orthologues hetero-oligomers in the early secretory pathway where they load onto zinc-requiring enzymes maintain functions. details this hetero-oligomerization remain to be elucidated, much more is known about homo-oligomerization that occurs other family proteins. Here, we addressed issue using co-immunoprecipitation experiments, mutagenesis, chimera studies hZnT5 hZnT6 chicken DT40 cells deficient...
The essential trace element zinc is important for all living organisms. Zinc functions not only as a nutritional factor, but also second messenger. However, the effects of intracellular on B cell-receptor (BCR) signaling pathway remain poorly understood. Here, we present data indicating that increase in level induced by ZIP9/SLC39A9 (a ZIP Zrt-/Irt-like protein) plays an role activation Akt and Erk response to BCR activation. In DT40 cells, enhancement phosphorylation following requires...
A number of enzymes become functional by binding to zinc during their journey through the early secretory pathway. The transporters (ZnTs) located there play important roles in this step. We have previously shown that two transport complexes, ZnT5/ZnT6 heterodimers and ZnT7 homo-oligomers, are required for activation alkaline phosphatases, converting them from apo- holo-form. Here, we investigated molecular mechanisms activation. ZnT1 ZnT4 expressed chicken DT40 cells did not contribute...
Given the relevance of beige adipocytes in adult humans, a better understanding molecular circuits involved adipocyte biogenesis has provided new insight into human brown biology. Genetic mutations SLC39A13/ZIP13, member zinc transporter family, are known to reduce adipose tissue mass humans; however, underlying mechanisms remains unknown. Here, we demonstrate that Zip13-deficient mouse shows enhanced and energy expenditure, ameliorated diet-induced obesity insulin resistance. Both gain-...
Understanding the mechanisms that regulate cellular identity and proliferation is crucial for elucidating functions. Under normal conditions, pancreatic endocrine cells express only a single hormone, their numbers are tightly regulated. Contrary to this general principle, our study revealed significant increase in glucagon (GCG) polypeptide (PP) double-positive (GCG + PP cells), along with hyperplasia of both α proglucagon-deficient mice. Similarly, systemic receptor-deficient mice exhibited...
Imeglimin and metformin act in metabolic organs, including β-cells, via different mechanisms. In the present study, we investigated impacts of imeglimin, metformin, or their combination (Imeg + Met) on liver, adipose tissues db/db mice. Imeglimin, Imeg Met treatment had no significant effects glucose tolerance, insulin sensitivity, respiratory exchange ratio, locomotor activity The responsiveness secretion to was recovered by treatment. Furthermore, increased β-cell mass enhancing...
Abstract Metal homeostasis is tightly regulated in cells and organisms, its disturbance frequently observed some diseases such as neurodegenerative metabolic disorders. Previous studies suggest that zinc iron are necessary for the normal functions of pancreatic β cells. However, distribution elements conditions pathophysiological significance dysregulated islet diabetic have remained unclear. In this study, to investigate dynamics islets a mouse model expressing human amyloid polypeptide...
Abstract Ehlers–Danlos syndrome spondylodysplastic type 3 (EDSSPD3, OMIM 612350) is an inherited recessive connective tissue disorder that caused by loss of function SLC39A13/ZIP13, a zinc transporter belonging to the Slc39a/ZIP family. We previously reported patients with EDSSPD3 harboring homozygous mutation (c.221G > A, p.G64D) in ZIP13 exon 2 ( G64D ) suffer from impaired development bone and tissues, muscular hypotonia. However, whether participates early differentiation these cell...
Numerous zinc ectoenzymes are metalated by and activated in the compartments of early secretory pathway before reaching their destination. Zn transporter (ZNT) proteins located these essential for ectoenzyme activation. We have previously reported that ZNT proteins, specifically ZNT5–ZNT6 heterodimers ZNT7 homodimers, play critical roles activation ectoenzymes, such as alkaline phosphatases (ALPs), mobilizing cytosolic into compartments. However, this process remains incompletely understood....
In Saccharomyces cerevisiae, the iron-responsive transcription factor Aft1p plays a critical role in maintaining iron homeostasis. The activity of is induced response to starvation and as consequence expression iron-regulon increased. We have shown previously that localized cytoplasm under iron-replete conditions but it nucleus iron-depleted conditions. this study, we identified transport receptor mediates import into nucleus, located nuclear localization signal (NLS) sequences Aft1p,...
Secretory and membrane-bound zinc-requiring enzymes are thought to be activated by binding zinc in the early secretory pathway. One such enzyme, tissue-non-specific alkaline phosphatase (TNAP), is through a two-step mechanism, via protein stabilization subsequent enzyme activation metalation, ZnT5-ZnT6 heterodimers or ZnT7 homodimers. However, little known about molecular basis underlying process. In present study, we found that di-proline motif (PP-motif) luminal loop 2 of ZnT5 important...
Abstract Pancreatic β-cell mass is known to be considerably altered during pregnancy and after parturition in rodents humans. While increases starts return toward its original level parturition, the cellular mechanisms by which this period regulated remains unclear. To address issue mice, we quantified investigated underlying regulation throughout perinatal postpartum period. The increased size proliferation were significantly reduced shortly whereas there was no evidence of reprogramming or...
Pancreatic polypeptide (PP) cells, which secrete PP (encoded by the Ppy gene), are a minor population of pancreatic endocrine cells. Although it has been reported that loss beta cell identity might be associated with beta-to-PP cell-fate conversion, at present, little is known regarding characteristics Ppy-lineage cells.We used Ppy-Cre driver mice and PP-specific monoclonal antibody to investigate association between cells The molecular profiles were investigated single-cell transcriptome...
Autophagy has been reported to play a crucial role in the maintenance of intracellular homeostasis, including pancreatic beta cells. Rubicon, which interacts with phosphoinositide 3-kinase (PI3K) complex, through autophagy-related 14 (ATG14), is among few autophagy regulators that have inhibit autophagic flux date and deletion Rubicon shown increase flux. Based on previous results showing causal relationship between dysfunction beta-cell impairment, we hypothesized cells would improve cell...
Recent studies have suggested that decreased pancreatic β-cell function and mass are common features of patients with type 2 diabetes mellitus. Pancreatic homeostasis is regulated by various types signaling molecules stress responses. Sequestosome 1/p62 (SQSTM1, hereafter referred to as p62) a ubiquitin-binding adaptor protein involved in cell signaling, oxidative stress, autophagy. Because p62 appears play an important role maintaining mitochondrial quality control, it possible the loss β...
Abstract The Ppy gene encodes pancreatic polypeptide (PP) secreted by PP‐ or γ‐cells, which are a subtype of endocrine cells localised mainly in the islet periphery. For detailed characterisation PP cells, we aimed to establish cell lines. To this end, generated mouse model harbouring SV40 large T antigen (TAg) Rosa26 locus, is expressed upon ‐promoter‐mediated Cre–loxP recombination. Whereas Insulin1 ‐ Cre ERT‐mediated TAg expression beta resulted insulinoma, surprisingly, ‐mediated...
Abstract Metabolic diseases are caused by a prolonged energy imbalance, and adipose tissue is known to be the main contributor. We previously reported that ZIP13, an Slc39a transporter whose deficiency causes Ehlers-Danlos syndrome spondylocheirodysplastic type 3 associated with lipoatrophy, inhibits adipocyte browning pathway modulating intracellular zinc status. The precise mechanisms of how ZIP13 regulates homeostasis remain unclear therefore, we investigated role in mature adipocytes...
Obesity is a health problem worldwide, and brown adipose tissue (BAT) important for energy expenditure. Here, we explored the role of leukotriene A4 hydrolase (LTA4 H), key enzyme in synthesis lipid mediator B4 (LTB4 ), diet-induced obesity. LTA4 H-deficient H-KO) mice fed high-fat diet (HFD) showed lean phenotype, bone-marrow transplantation studies revealed that H-deficiency non-hematopoietic cells was responsible this phenotype. H-KO exhibited greater expenditure, but similar food intake...