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INTRACELLULAR MECHANISMS INVOLVED IN THE INDUCTION OF
HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) - INDUCED
SKELETAL MUSCLE INSULIN RESISTANCE AND POTENTIAL
THERAPEUTIC APPROACHES TO INCREASE INSULIN SENSITIVITY
by
Lindsey Davis Bogachus
________________________________________________________________________
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(INTEGRATIVE AND EVOLUTIONARY BIOLOGY)
August 2011
Copyright 2011 Lindsey Davis Bogachus
Object Description
| Title | Intracellular mechanisms involved in the induction of highly active antiretroviral therapy (HAART) - induced skeletal muscle insulin resistance and potential therapeutic approaches to increase insulin sensitivity |
| Author | Bogachus, Lindsey Davis |
| Author email | bogachus@usc.edu;bogey5344@aol.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Integrative and Evolutionary Biology |
| School | College of Letters, Arts And Sciences |
| Date defended/completed | 2011-05-30 |
| Date submitted | 2011-07-06 |
| Date approved | 2011-07-06 |
| Restricted until | 2011-07-06 |
| Date published | 2011-07-06 |
| Advisor (committee chair) | Turcotte, Lorraine P. |
| Advisor (committee member) |
McNitt-Gray, Jill L. Wong, Hung Leung |
| Abstract | The contents of this dissertation contain three experiments aimed at determining the intracellular mechanisms involved in the induction of highly active antiretroviral therapy (HAART)-induced skeletal muscle insulin resistance and potential therapeutic approaches to increase insulin sensitivity. ❧ The data from the first study indicate that the insulin sensitizing agent, metformin, activates AMPKα₁ preferentially over AMPKα₂ in skeletal muscle cells. Additionally, the metformin treated groups had decreased rates of FA uptake and oxidation when compared to control cells. Interestingly, in the metformin treated groups, the FA transport protein CD36 was similarly decreased with FA uptake, however, a key regulator of FA oxidation, ACC, did not have reduced phosphorylation with metformin treatment. Furthermore, metformin treatment increased SIRT1 activity and decreased PGC-1α acetylation indicating cross-talk between AMPK and SIRT1. Additional data using genetically modified cells with decreased AMPKα₁ or AMPKα₂ phosphorylation potential provide further evidence for the preferential phosphorylation of AMPKα₁ with metformin treatment. Together these results suggest that multiple signaling cascades including AMPK and SIRT1 may regulate metformin-induced glucose and FA metabolism in skeletal muscle cells. ❧ The data from the second study indicate that atazanavir sulfate+ritonavir treatment significantly increase glucose uptake and FA uptake and oxidation while inducing insulin resistance in the skeletal muscle cells. Inflammation may play a significant role in atazanavir sulfate+ritonavir-induced insulin resistance since JNK1/2 pro-inflammatory signaling was significantly upregulated when compared to control cells. Interestingly, when atazanavir sulfate and ritonavir were incubated individually, only the atazanavir sulfate treated cells had increased JNK1/2 phosphorylation state. Unexpectedly, p38 MAPK, another pro-inflammatory marker, was not upregulated with atazanavir sulfate, ritonavir, or atazanavir sulfate+ritonavir treatment indicating p38 MAPK signaling does not play a significant role in atazanavir sulfate+ritonavir-induced insulin resistance. Together these results suggest that atazanavir sulfate+ritonavir induce metabolic dysfunction in part via increased JNK1/2 pro-inflammatory signaling in skeletal muscle cells. ❧ The data from the third study indicate that both metformin and resveratrol treatment significantly decreases glucose uptake in atazanavir sulfate+ritonavir-induced insulin resistant cells and concomitantly increases skeletal muscle insulin sensitivity. Additionally, while metformin had no effect on the rate of FA uptake, resveratrol treatment significantly reduced atazanavir sulfate+ritonavir-induced FA uptake when compared to atazanavir sulfate+ritonavir treated cells. Interestingly, atazanavir sulfate+ritonavir-induced FA oxidation rates were not changed with metformin or resveratrol treatment. However, the addition of either metformin or resveratrol to insulin stimulated atazanavir sulfate+ritonavir treated cells increased AKTser473 phosphorylation significantly more than atazanavir sulfate+ritonavir treated cells alone, indicating increased insulin sensitivity. Along those lines, treatment with metformin or resveratrol significantly decreased atazanavir sulfate+ritonavir-induced JNK1/2 pro-inflammatory signaling, which indicate decreased inflammation in the skeletal muscle cells. Thus, since inflammation has been shown to play a significant role in the induction of insulin resistance, decreased inflammation may suggest increased insulin sensitivity. Finally, and in line with the second study, p38 MAPK phosphorylation state was not altered with metformin or resveratrol treatment in the atazanavir sulfate+ritonavir treatment groups or in the basal state with metformin or resveratrol treatment alone indicating that p38 MAPK does not play a significant role in atazanavir sulfate+ritonavir-induced skeletal muscle insulin resistance. Since JNK1/2 was significantly upregulated with induction of insulin resistance in atazanavir sulfate+ritonavir treated cells, the necessity of JNK1/2 upregulation for induction of atazanavir sulfate+ritonavir-induced insulin resistance was investigated via, the JNK1/2 inhibitor, SP600125. SP600125 treatment significantly decreased atazanavir sulfate+ritonavir-induced glucose uptake and restored insulin sensitivity. Additionally, SP600125 completely eliminated the atazanavir sulfate+ritonavir-induced increase in FA uptake while partially eliminating the atazanavir sulfate+ritonavir-induced increase in FA oxidation. As expected, and similar to metformin and resveratrol treatment, SP600125 significantly reduced JNK1/2 phosphorylation in atazanavir sulfate+ritonavir treated cells indicating decreased inflammation. Together these results suggest that both metformin and resveratrol are effective insulin sensitizing agents that are capable of blunting atazanavir sulfate+ritonavir-induced insulin resistance in skeletal muscle cells. ❧ All data, taken together, indicate that atazanavir sulfate+ritonavir induce metabolic dysregulation and insulin resistance in skeletal muscle cells. Furthermore, that inflammation plays a significant role in atazanavir sulfate+ritonavir-induced skeletal muscle insulin resistance. Finally, insulin sensitizing agents such as metformin and resveratrol may be capable of blunting atazanavir sulfate+ritonavir-induced skeletal muscle insulin resistance thus restoring metabolic regulation. |
| Keyword | glucose uptake; 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR); Silent mating-type Information Regulator 2 homolog 1 (SIRT1); FAT/CD36; Glut4; p38 MAPK (Mitogen Activated Protein Kinase); inflammation; AKT2; fatty acid oxidation; SP600125 |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Contributing entity | University of Southern California |
| Rights | Bogachus, Lindsey Davis |
| Physical access | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@dots.usc.edu |
| Archival file | uscthesesreloadpub_Volume71/etd-BogachusLi-50.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@dots.usc.edu |
| Full text | INTRACELLULAR MECHANISMS INVOLVED IN THE INDUCTION OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART) - INDUCED SKELETAL MUSCLE INSULIN RESISTANCE AND POTENTIAL THERAPEUTIC APPROACHES TO INCREASE INSULIN SENSITIVITY by Lindsey Davis Bogachus ________________________________________________________________________ A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (INTEGRATIVE AND EVOLUTIONARY BIOLOGY) August 2011 Copyright 2011 Lindsey Davis Bogachus |
