Person:
Chutkow, William

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Chutkow

First Name

William

Name

Chutkow, William
Author's Publications: search.filters.isAuthorOfPublication.18b801f3-b6c4-4f0e-8178-869c64e44da2

Search Results

Now showing 1 - 2 of 2
  • Thumbnail Image
    Publication
    Thioredoxin-interacting protein regulates protein disulfide isomerases and endoplasmic reticulum stress
    (Blackwell Publishing Ltd, 2014) Lee, Samuel; Min Kim, Soo; Dotimas, James; Li, Tish; Feener, Edward Paul; Baldus, Stephan; Myers, Ronald B; Chutkow, William; Patwari, Parth; Yoshioka, Jun; Lee, Richard
    The endoplasmic reticulum (ER) is responsible for protein folding, modification, and trafficking. Accumulation of unfolded or misfolded proteins represents the condition of ER stress and triggers the unfolded protein response (UPR), a key mechanism linking supply of excess nutrients to insulin resistance and type 2 diabetes in obesity. The ER harbors proteins that participate in protein folding including protein disulfide isomerases (PDIs). Changes in PDI activity are associated with protein misfolding and ER stress. Here, we show that thioredoxin-interacting protein (Txnip), a member of the arrestin protein superfamily and one of the most strongly induced proteins in diabetic patients, regulates PDI activity and UPR signaling. We found that Txnip binds to PDIs and increases their enzymatic activity. Genetic deletion of Txnip in cells and mice led to increased protein ubiquitination and splicing of the UPR regulated transcription factor X-box-binding protein 1 (Xbp1s) at baseline as well as under ER stress. Our results reveal Txnip as a novel direct regulator of PDI activity and a feedback mechanism of UPR signaling to decrease ER stress.
  • Thumbnail Image
    Publication
    TXNIP Regulates Peripheral Glucose Metabolism in Humans
    (Public Library of Science, 2007) Parikh, Hemang; Carlsson, Emma; Johansson, Lovisa E; Storgaard, Heidi; Poulsen, Pernille; Ladd, Christine; Schulze, P. Christian; Mazzini, Michael J; Jensen, Christine Bjørn; Krook, Anna; Björnholm, Marie; Tornqvist, Hans; Zierath, Juleen R; Ridderstråle, Martin; Vaag, Allan; Groop, Leif C; Chutkow, William; Saxena, Richa; Altshuler, David; Lee, Richard; Mootha, Vamsi
    Background: Type 2 diabetes mellitus (T2DM) is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure. Methods and Findings: We combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein (TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated to total body measures of glucose uptake. Forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that the gene product is also a regulator of glucose uptake. TXNIP expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM. Conclusions: TXNIP regulates both insulin-dependent and insulin-independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic β-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM.