PID1 regulates insulin-dependent glucose uptake by controlling intracellular sorting of GLUT4-storage vesicles
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PID1 regulates insulin-dependent glucose uptake by controlling intracellular sorting of GLUT4-storage vesicles. / Fischer, Alexander W; Albers, Kirstin; Schlein, Christian; Sass, Frederike; Krott, Lucia M; Schmale, Hartwig; Gordts, Philip L S M; Scheja, Ludger; Heeren, Joerg.
In: BBA-MOL BASIS DIS, Vol. 1865, No. 6, 01.06.2019, p. 1592-1603.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - PID1 regulates insulin-dependent glucose uptake by controlling intracellular sorting of GLUT4-storage vesicles
AU - Fischer, Alexander W
AU - Albers, Kirstin
AU - Schlein, Christian
AU - Sass, Frederike
AU - Krott, Lucia M
AU - Schmale, Hartwig
AU - Gordts, Philip L S M
AU - Scheja, Ludger
AU - Heeren, Joerg
N1 - Copyright © 2019 Elsevier B.V. All rights reserved.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - The phosphotyrosine interacting domain-containing protein 1 (PID1) serves as a cytosolic adaptor protein of the LDL receptor-related protein 1 (LRP1). By regulating its intracellular trafficking, PID1 controls the hepatic, LRP1-dependent clearance of pro-atherogenic lipoproteins. In adipose and muscle tissues, LRP1 is present in endosomal storage vesicles containing the insulin-responsive glucose transporter 4 (GLUT4). This prompted us to investigate whether PID1 modulates GLUT4 translocation and function via its interaction with the LRP1 cytosolic domain. We initially evaluated this in primary brown adipocytes as we observed an inverse correlation between brown adipose tissue glucose uptake and expression of LRP1 and PID1. Insulin stimulation in wild type brown adipocytes induced LRP1 and GLUT4 translocation from endosomal storage vesicles to the cell surface. Loss of PID1 expression in brown adipocytes prompted LRP1 and GLUT4 sorting to the plasma membrane independent of insulin signaling. When placed on a diabetogenic high fat diet, systemic and adipocyte-specific PID1-deficient mice presented with improved hyperglycemia and glucose tolerance as well as reduced basal plasma insulin levels compared to wild type control mice. Moreover, the improvements in glucose parameters associated with increased glucose uptake in adipose and muscle tissues from PID1-deficient mice. The data provide evidence that PID1 serves as an insulin-regulated retention adaptor protein controlling translocation of LRP1 in conjunction with GLUT4 to the plasma membrane of adipocytes. Notably, loss of PID1 corrects for insulin resistance-associated hyperglycemia emphasizing its pivotal role and therapeutic potential in the regulation of glucose homeostasis.
AB - The phosphotyrosine interacting domain-containing protein 1 (PID1) serves as a cytosolic adaptor protein of the LDL receptor-related protein 1 (LRP1). By regulating its intracellular trafficking, PID1 controls the hepatic, LRP1-dependent clearance of pro-atherogenic lipoproteins. In adipose and muscle tissues, LRP1 is present in endosomal storage vesicles containing the insulin-responsive glucose transporter 4 (GLUT4). This prompted us to investigate whether PID1 modulates GLUT4 translocation and function via its interaction with the LRP1 cytosolic domain. We initially evaluated this in primary brown adipocytes as we observed an inverse correlation between brown adipose tissue glucose uptake and expression of LRP1 and PID1. Insulin stimulation in wild type brown adipocytes induced LRP1 and GLUT4 translocation from endosomal storage vesicles to the cell surface. Loss of PID1 expression in brown adipocytes prompted LRP1 and GLUT4 sorting to the plasma membrane independent of insulin signaling. When placed on a diabetogenic high fat diet, systemic and adipocyte-specific PID1-deficient mice presented with improved hyperglycemia and glucose tolerance as well as reduced basal plasma insulin levels compared to wild type control mice. Moreover, the improvements in glucose parameters associated with increased glucose uptake in adipose and muscle tissues from PID1-deficient mice. The data provide evidence that PID1 serves as an insulin-regulated retention adaptor protein controlling translocation of LRP1 in conjunction with GLUT4 to the plasma membrane of adipocytes. Notably, loss of PID1 corrects for insulin resistance-associated hyperglycemia emphasizing its pivotal role and therapeutic potential in the regulation of glucose homeostasis.
KW - Adipocytes, Brown/metabolism
KW - Adipose Tissue, Brown/metabolism
KW - Animals
KW - Biological Transport
KW - Carrier Proteins/genetics
KW - Cell Membrane/metabolism
KW - Diet, High-Fat/adverse effects
KW - Endosomes/metabolism
KW - Gene Expression Regulation
KW - Glucose/metabolism
KW - Glucose Transporter Type 4/genetics
KW - Homeostasis/genetics
KW - Insulin/metabolism
KW - Insulin Resistance
KW - Liver/metabolism
KW - Low Density Lipoprotein Receptor-Related Protein-1/genetics
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Transgenic
KW - Muscle, Skeletal/metabolism
KW - Obesity/etiology
KW - Primary Cell Culture
KW - Signal Transduction
U2 - 10.1016/j.bbadis.2019.03.010
DO - 10.1016/j.bbadis.2019.03.010
M3 - SCORING: Journal article
C2 - 30904610
VL - 1865
SP - 1592
EP - 1603
JO - BBA-MOL BASIS DIS
JF - BBA-MOL BASIS DIS
SN - 0925-4439
IS - 6
ER -