PID1 regulates insulin-dependent glucose uptake by controlling intracellular sorting of GLUT4-storage vesicles

TY - JOUR

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 -