scholarly journals TXNIP/TBP-2: A Master Regulator for Glucose Homeostasis

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 765
Author(s):  
Eiji Yoshihara
Keyword(s):  
Glucose Homeostasis ◽  
Whole Body ◽  
Cellular Functions ◽  
Master Regulator ◽  
Independent Manner ◽  
Interacting Protein ◽  
Regulatory Pathways ◽  
Thioredoxin Interacting Protein ◽  
Important Regulator ◽  
Future Direction

Identification of thioredoxin binding protein-2 (TBP-2), which is currently known as thioredoxin interacting protein (TXNIP), as an important binding partner for thioredoxin (TRX) revealed that an evolutionarily conserved reduction-oxidation (redox) signal complex plays an important role for pathophysiology. Due to the reducing activity of TRX, the TRX/TXNIP signal complex has been shown to be an important regulator for redox-related signal transduction in many types of cells in various species. In addition to its role in redox-dependent regulation, TXNIP has cellular functions that are performed in a redox-independent manner, which largely rely on their scaffolding function as an ancestral α-Arrestin family. Both the redox-dependent and -independent TXNIP functions serve as regulatory pathways in glucose metabolism. This review highlights the key advances in understanding TXNIP function as a master regulator for whole-body glucose homeostasis. The potential for therapeutic advantages of targeting TXNIP in diabetes and the future direction of the study are also discussed.

scholarly journals Loss of CHIP Expression Perturbs Glucose Homeostasis and Leads to Type II Diabetes through Defects in Microtubule Polymerization and Glucose Transporter Localization

2017 ◽  
Author(s):  
Holly McDonough ◽  
Kaitlin C. Lenhart ◽  
Sarah M. Ronnebaum ◽  
Chunlian Zhang ◽  
Jie An ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Protein Trafficking ◽  
Type Ii Diabetes ◽  
Glucose Transporter ◽  
Protein A ◽  
Whole Body ◽  
Type Ii ◽  
Interacting Protein ◽  
Microtubule Polymerization ◽  
Dependent Protein

ABSTRACTRecent evidence has implicated CHIP (carboxyl terminus of Hsc/Hsp70-interacting protein), a co-chaperone and ubiquitin ligase, in the functional support of several metabolism-related proteins, including AMPK and SirT6. In addition to previously reported aging and stress intolerance phenotypes, we find that CHIP -/- mice also demonstrate a Type II diabetes-like phenotype, including poor glucose tolerance, decreased sensitivity to insulin, and decreased insulin-stimulated glucose uptake in isolated skeletal muscle, characteristic of insulin resistance. In CHIP-deficient cells, glucose stimulation fails to induce translocation of Glut4 to the plasma membrane. This impairment in Glut4 translocation in CHIP-deficient cells is accompanied by decreased tubulin polymerization associated with decreased phosphorylation of stathmin, a microtubule-associated protein required for polymerization-dependent protein trafficking within the cell. Together, these data describe a novel role for CHIP in regulating microtubule polymerization that assists in glucose transporter translocation, promoting whole-body glucose homeostasis and sensitivity to insulin.

scholarly journals The death domain kinase RIP1 links the immunoregulatory CD40 receptor to apoptotic signaling in carcinomas

2011 ◽  
Vol 192 (3) ◽  
pp. 391-399 ◽  
Author(s):  
Pauline G. Knox ◽  
Clare C. Davies ◽  
Marina Ioannou ◽  
Aristides G. Eliopoulos
Keyword(s):  
Adaptor Protein ◽  
Cd40 Ligand ◽  
Tnf Receptor ◽  
Death Domain ◽  
Apoptosis Induction ◽  
Cellular Functions ◽  
Cd40 Ligation ◽  
Interacting Protein ◽  
Regulatory Pathways ◽  
Signaling Complex

CD40, a tumor necrosis factor (TNF) receptor family member, is widely recognized for its prominent role in the antitumor immune response. The immunostimulatory effects of CD40 ligation on malignant cells can be switched to apoptosis upon disruption of survival signals transduced by the binding of the adaptor protein TRAF6 to CD40. Apoptosis induction requires a TRAF2-interacting CD40 motif but is initiated within a cytosolic death-inducing signaling complex after mobilization of receptor-bound TRAF2 to the cytoplasm. We demonstrate that receptor-interacting protein 1 (RIP1) is an integral component of this complex and is required for CD40 ligand-induced caspase-8 activation and tumor cell killing. Degradation of the RIP1 K63 ubiquitin ligases cIAP1/2 amplifies the CD40-mediated cytotoxic effect, whereas inhibition of CYLD, a RIP1 K63 deubiquitinating enzyme, reduces it. This two-step mechanism of apoptosis induction expands our appreciation of commonalities in apoptosis regulatory pathways across the TNF receptor superfamily and provides a telling example of how TNF family receptors usurp alternative programs to fulfill distinct cellular functions.

scholarly journals Regulation of plasma triglyceride partitioning by adipose-derived ANGPTL4 in mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kathryn M. Spitler ◽  
Shwetha K. Shetty ◽  
Emily M. Cushing ◽  
Kelli L. Sylvers-Davie ◽  
Brandon S. J. Davies
Keyword(s):  
Glucose Homeostasis ◽  
High Fat Diet ◽  
Normal Diet ◽  
Plasma Triglyceride ◽  
Whole Body ◽  
Activity Levels ◽  
High Fat ◽  
Important Regulator ◽  
Fat Feeding

AbstractElevated plasma triglyceride levels are associated with metabolic disease. Angiopoietin-like protein 4 (ANGPTL4) regulates plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). Our aim was to investigate the role of adipocyte-specific deficiency of ANGPTL4 in mice during high fat diet feeding. Adipocyte-specific ANGPTL4 deficient mice were fed a high fat diet (60% kCal from fat) for either 12 weeks or 6 months. We performed plasma metabolic measurements, triglyceride clearance and uptake assays, LPL activity assays, and assessed glucose homeostasis. Mice lacking adipocyte ANGPTL4 recapitulated the triglyceride phenotypes of whole-body ANGPTL4 deficiency, including increased adipose LPL activity, lower plasma triglyceride levels, and increased uptake of triglycerides into adipose tissue. When fed a high fat diet (HFD), these mice continued to display enhanced adipose LPL activity and initially had improved glucose and insulin sensitivity. However, after 6 months on HFD, the improvements in glucose homeostasis were largely lost. Moreover, despite higher adipose LPL activity levels, mice lacking adipocyte ANGPTL4 no longer had increased triglyceride uptake into adipose compared to littermate controls after chronic high-fat feeding. These observations suggest that after chronic high-fat feeding LPL is no longer rate-limiting for triglyceride delivery to adipocytes. We conclude that while adipocyte-derived ANGPTL4 is an important regulator of plasma triglyceride levels and triglyceride partitioning under normal diet conditions, its role is diminished after chronic high-fat feeding.

Abstract 14774: Rescue of Diabetes-related Impairment of Ischemia-mediated Neovascularization With Fenofibrate Treatment

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Kushwin Rajamani ◽  
Jun Yuan ◽  
Laura Lecce ◽  
Alicia Jenkins ◽  
Anthony Keech ◽  
...  
Keyword(s):  
Blood Flow ◽  
Drug Targets ◽  
Capillary Density ◽  
Protective Effects ◽  
Hindlimb Ischemia ◽  
Independent Manner ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Independent Mechanism

Background: Fenofibrate, a PPARα agonist, reduced amputation events in the Fenofibrate Intervention and Event Lowering in Diabetes study among 9795 patients, the mechanisms of which are unknown. We hypothesised that fenofibrate may attenuate diabetes-related impairment in ischemia-mediated neovascularization. Methods: Hindlimb ischemia was induced in a murine model of streptozotocin induced diabetes mellitus (DM) in wildtype and PPARα receptor knockout mice (KO) with/without fenofibrate (30mg/kg/day in high fat diet). Ischemic recovery was assessed by laser doppler, foot movement and capillary density analysis. Key angiogenic events (tubulogenesis) and expression of thioredoxin-interacting protein (TXNIP) mRNA and protein following normal and high glucose (5 vs 25mM glucose) environments were determined in cultured endothelial cells (ECs), with/without selective PPARα receptor antagonist (10μM MK886) and agonist (10μM WY14643). Results: DM profoundly impaired blood flow recovery following hindlimb ischemia (0.51±0.04[n=5] vs 0.34±0.03[n=5];p<0.001). Fenofibrate (FF) restored DM-related impairment in blood flow recovery (0.53±0.04[n=5] vs 0.34±0.03[n=5];p<0.01), capillary density (1.48±0.03 vs1.20±0.04;p<0.01), foot movement scores to levels of non-diabetic controls. Similar findings for fenofibrate were observed in diabetic PPARα KO mice. In vitro, fenofibric acid (FA) rescued hyperglycemia-induced impairment in EC tubulogenesis (87.8 vs 58.3% of control;p<0.05) by a PPARα-independent mechanism. FA prevented hyperglycemia-induced overexpression of TXNIP (mRNA: 1.20±0.16 vs 1.84±0.28 folds of control;p<0.01) an exquisitely glucose-sensitive regulator of angiogenesis, in a PPARα-independent manner. Furthermore, overexpression of TXNIP abrogated the protective effects of FA. Conclusions: Fenofibrate rescues diabetic impairment in ischemia-mediated angiogenesis via a largely PPARα-independent mechanism. Improved neovascularization may therefore explain in part the reduced amputations seen with fenofibrate in type 2 diabetes. These findings provide a novel mechanistic understanding for fenofibrate action and may provide a platform for new drug targets.

Thermoneutral housing does not influence fat mass or glucose homeostasis in C57BL/6 mice

2018 ◽  
Vol 239 (3) ◽  
pp. 313-324 ◽  
Author(s):  
Lewin Small ◽  
Henry Gong ◽  
Christian Yassmin ◽  
Gregory J Cooney ◽  
Amanda E Brandon
Keyword(s):  
Glucose Metabolism ◽  
Ambient Temperature ◽  
Fat Mass ◽  
Glucose Homeostasis ◽  
Dietary Intervention ◽  
Whole Body ◽  
Housing Temperature ◽  
Brown Adipose ◽  
Normal Chow ◽  
Obesogenic Diet

One major factor affecting physiology often overlooked when comparing data from animal models and humans is the effect of ambient temperature. The majority of rodent housing is maintained at ~22°C, the thermoneutral temperature for lightly clothed humans. However, mice have a much higher thermoneutral temperature of ~30°C, consequently data collected at 22°C in mice could be influenced by animals being exposed to a chronic cold stress. The aim of this study was to investigate the effect of housing temperature on glucose homeostasis and energy metabolism of mice fed normal chow or a high-fat, obesogenic diet (HFD). Male C57BL/6J(Arc) mice were housed at standard temperature (22°C) or at thermoneutrality (29°C) and fed either chow or a 60% HFD for 13 weeks. The HFD increased fat mass and produced glucose intolerance as expected but this was not exacerbated in mice housed at thermoneutrality. Changing the ambient temperature, however, did alter energy expenditure, food intake, lipid content and glucose metabolism in skeletal muscle, liver and brown adipose tissue. Collectively, these findings demonstrate that mice regulate energy balance at different housing temperatures to maintain whole-body glucose tolerance and adiposity irrespective of the diet. Despite this, metabolic differences in individual tissues were apparent. In conclusion, dietary intervention in mice has a greater impact on adiposity and glucose metabolism than housing temperature although temperature is still a significant factor in regulating metabolic parameters in individual tissues.

1971-P: Activation of Adipocyte Gq Signaling Causes Improved Whole-Body Glucose Homeostasis

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1971-P
Author(s):  
TAKEFUMI KIMURA ◽  
SAI PRASAD PYDI ◽  
LEI WANG ◽  
YINGHONG CUI ◽  
OKSANA GAVRILOVA ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Whole Body

scholarly journals MYH9-dependent polarization of ATG9B promotes colorectal cancer metastasis by accelerating focal adhesion assembly

2021 ◽  
Author(s):  
Yan Zhong ◽  
Ting Long ◽  
Chuan-Sha Gu ◽  
Jing-Yi Tang ◽  
Ling-Fang Gao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Focal Adhesion ◽  
Poor Prognosis ◽  
Cancer Metastasis ◽  
Integrin Β1 ◽  
Independent Manner ◽  
Interacting Protein ◽  
Tumour Metastasis ◽  
Elevated Expression ◽  
Dependent Polarization

AbstractTumour metastasis is a major reason accounting for the poor prognosis of colorectal cancer (CRC), and the discovery of targets in the primary tumours that can predict the risk of CRC metastasis is now urgently needed. In this study, we identified autophagy-related protein 9B (ATG9B) as a key potential target gene for CRC metastasis. High expression of ATG9B in tumour significantly increased the risk of metastasis and poor prognosis of CRC. Mechanistically, we further find that ATG9B promoted CRC invasion mainly through autophagy-independent manner. MYH9 is the pivotal interacting protein for ATG9B functioning, which directly binds to cytoplasmic peptide segments aa368–411 of ATG9B by its head domain. Furthermore, the combination of ATG9B and MYH9 enhance the stability of each other by decreasing their binding to E3 ubiquitin ligase STUB1, therefore preventing them from ubiquitin-mediated degradation, which further amplified the effect of ATG9B and MYH9 in CRC cells. During CRC cell invasion, ATG9B is transported to the cell edge with the assistance of MYH9 and accelerates focal adhesion (FA) assembly through mediating the interaction of endocytosed integrin β1 and Talin-1, which facilitated to integrin β1 activation. Clinically, upregulated expression of ATG9B in human CRC tissue is always accompanied with highly elevated expression of MYH9 and associated with advanced CRC stage and poor prognosis. Taken together, this study highlighted the important role of ATG9B in CRC metastasis by promoting focal adhesion assembly, and ATG9B together with MYH9 can provide a pair of potential therapeutic targets for preventing CRC progression.

miR-125b enhances metastasis and progression of cancer via the TXNIP and HIF1α pathway in pancreatic cancer

2021 ◽  
pp. 1-12
Author(s):  
Pengli Wang ◽  
Dan Zheng ◽  
Hongyang Qi ◽  
Qi Gao
Keyword(s):  
Pancreatic Cancer ◽  
Hypoxia Inducible Factor ◽  
Immunofluorescence Assay ◽  
Luciferase Assay ◽  
Interacting Protein ◽  
Over Expression ◽  
Thioredoxin Interacting Protein ◽  
Cellular Processes ◽  
And Migration

BACKGROUND: MicroRNAs (miRNAs) play potential role in the development of various types of cancer conditions including pancreatic cancer (PC) targeting several cellular processes. Present study was aimed to evaluate function of miR-125b and the mechanism involved in PC. METHODS: Cell migration, MTT and BrdU study was done to establish the migration capability, cell viability and cell proliferation respectively. Binding sites for miR-125b were recognized by luciferase assay, expression of protein by western blot and immunofluorescence assay. In vivo study was done by BALB/c nude xenograft mice for evaluating the function of miR-125b. RESULTS: The study showed that expression of miR-125b was elevated in PC cells and tissues, and was correlated to proliferation and migration of cells. Also, over-expression of miR-125b encouraged migration, metastasis and proliferation of BxPC-3 cells, the suppression reversed it. We also noticed that thioredoxin-interacting protein (TXNIP) was the potential target of miR-125b. The outcomes also suggested that miR-125b governed the expression of TXNIP inversely via directly attaching to the 3′-UTR activating hypoxia-inducible factor 1α (HIF1α). Looking into the relation between HIF1α and TXNIP, we discovered that TXNIP caused the degradation and export of HIF1α by making a complex with it. CONCLUSION: The miR-125b-TXNIP-HIF1α pathway may serve useful strategy for diagnosing and treating PC.

scholarly journals 374 Thioredoxin, thioredoxin interacting protein and galectin-3 in preeclampsia

2021 ◽  
Vol 224 (2) ◽  
pp. S243-S244
Author(s):  
Sivan Farladansky-Gershnabel ◽  
Ishai Heusler ◽  
Tal Biron-Shental ◽  
Keren Cohen-Hagai ◽  
Sydney Benchetrit ◽  
...  
Keyword(s):  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Galectin 3
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