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Regulation of the Actin Cytoskeleton by Palmitate : = Implications for Lymphatic Endothelial Barrier Function and Skeletal Muscle GLUT4 Translocation.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Regulation of the Actin Cytoskeleton by Palmitate :/
Reminder of title:	Implications for Lymphatic Endothelial Barrier Function and Skeletal Muscle GLUT4 Translocation.
Author:	Tokarz, Victoria L.
Description:	1 online resource (280 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-05, Section: B.
Contained By:	Dissertations Abstracts International85-05B.
Subject:	Cellular biology. -
Online resource:	click for full text (PQDT)
ISBN:	9798380839846

Regulation of the Actin Cytoskeleton by Palmitate : = Implications for Lymphatic Endothelial Barrier Function and Skeletal Muscle GLUT4 Translocation.
Tokarz, Victoria L.

Regulation of the Actin Cytoskeleton by Palmitate :Implications for Lymphatic Endothelial Barrier Function and Skeletal Muscle GLUT4 Translocation. - 1 online resource (280 pages)

Source: Dissertations Abstracts International, Volume: 85-05, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2023.

Includes bibliographical references

The actin cytoskeleton is a critical component of cells that regulates core cellular processes in diverse cell types. It provides structural and mechanical support, regulates intracellular trafficking, mediates contacts between cells and more. During the development of obesity, cells are exposed to increasing levels of saturated fatty acids (SFAs). SFAs have been implicated in the development of two obesity-associated disorders that I was interested in investigating: lymphatic dysfunction and skeletal muscle insulin resistance, but their precise impact on the actin cytoskeleton in the lymphatic endothelium and skeletal muscle and how it alters their canonical functions (fluid homeostasis and glucose disposal) is incompletely understood.In this dissertation, I identify the actin cytoskeleton as a target of the SFA palmitate (PA) that confers cell type-specific dysfunction in both lymphatic endothelial cells and skeletal muscle cells. In Chapter 3, I describe how PA, but not its unsaturated counterpart palmitoleate (PO), alters the lymphatic endothelial junction by remodelling the actin cytoskeleton. I detail how PA caused the accumulation of actin stress fibres that disrupted cell-cell contacts and compromised wound healing. In Chapter 4, I outline how PA impaired GLUT4 translocation in skeletal muscle cells by abrogating insulin-stimulated actin remodelling and by disrupting the intracellular trafficking of GLUT4. Moreover, I determined that the failure of actin remodelling and GLUT4 mis-localization in these cells are governed by distinct mechanisms, endoplasmic reticulum stress and protein palmitoylation, respectively. In Chapter 5, I uncovered a previously unappreciated role for complexin-2 in insulin-stimulated GLUT4 vesicle fusion with the plasma membrane in skeletal muscle cells that requires actin remodelling.This work establishes PA as a regulator of the actin cytoskeleton in two cell types with unique functional implications for each. My work advances our understanding of how SFAs regulate the cellular actin architecture and how these alterations confer cell type-specific dysfunction. While my work focused on only two cell types, it provides compelling initial evidence that SFA mediated dysregulation of the actin cytoskeleton may represent a common mechanism underlying cellular dysfunction during nutritional excess in additional cell types.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798380839846Subjects--Topical Terms:

1148666
Cellular biology.
Subjects--Index Terms:

Actin cytoskeletonIndex Terms--Genre/Form:

554714
Electronic books.

Regulation of the Actin Cytoskeleton by Palmitate : = Implications for Lymphatic Endothelial Barrier Function and Skeletal Muscle GLUT4 Translocation.
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520 $a The actin cytoskeleton is a critical component of cells that regulates core cellular processes in diverse cell types. It provides structural and mechanical support, regulates intracellular trafficking, mediates contacts between cells and more. During the development of obesity, cells are exposed to increasing levels of saturated fatty acids (SFAs). SFAs have been implicated in the development of two obesity-associated disorders that I was interested in investigating: lymphatic dysfunction and skeletal muscle insulin resistance, but their precise impact on the actin cytoskeleton in the lymphatic endothelium and skeletal muscle and how it alters their canonical functions (fluid homeostasis and glucose disposal) is incompletely understood.In this dissertation, I identify the actin cytoskeleton as a target of the SFA palmitate (PA) that confers cell type-specific dysfunction in both lymphatic endothelial cells and skeletal muscle cells. In Chapter 3, I describe how PA, but not its unsaturated counterpart palmitoleate (PO), alters the lymphatic endothelial junction by remodelling the actin cytoskeleton. I detail how PA caused the accumulation of actin stress fibres that disrupted cell-cell contacts and compromised wound healing. In Chapter 4, I outline how PA impaired GLUT4 translocation in skeletal muscle cells by abrogating insulin-stimulated actin remodelling and by disrupting the intracellular trafficking of GLUT4. Moreover, I determined that the failure of actin remodelling and GLUT4 mis-localization in these cells are governed by distinct mechanisms, endoplasmic reticulum stress and protein palmitoylation, respectively. In Chapter 5, I uncovered a previously unappreciated role for complexin-2 in insulin-stimulated GLUT4 vesicle fusion with the plasma membrane in skeletal muscle cells that requires actin remodelling.This work establishes PA as a regulator of the actin cytoskeleton in two cell types with unique functional implications for each. My work advances our understanding of how SFAs regulate the cellular actin architecture and how these alterations confer cell type-specific dysfunction. While my work focused on only two cell types, it provides compelling initial evidence that SFA mediated dysregulation of the actin cytoskeleton may represent a common mechanism underlying cellular dysfunction during nutritional excess in additional cell types.
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