Abstract

Lipotoxicity is a response to lipid overload that has been associated with cellular dysfunction leading to cellular death. The mechanism of lipotoxicity and its impact on the nervous system is critical as it can lead to debilitating neurological conditions. This study examines key cellular events induced by palmitic acid lipotoxicity (PA-LTx) in Schwann cells cultured in euglycemic and hyperglycemic conditions. The data show that immortalized Schwann cell (iSC), as well as primary Schwann cell (pSC) cultures exposed to elevated levels of PA induced an apoptotic cell death that is dose and time-dependent. The earliest indication of cellular dysfunction was a decrease in Ca++ levels in the endoplasmic reticulum (ER, [Ca++] ER). This decrease in [Ca++ ]ER was associated with a significant change in the expression of ER stress signature genes such as CHOP, Xbp1 and GRP78. In SC cultured in euglycemic conditions, lysosomal membrane destabilization preceded mitochondrial membrane depolarization, oxidative stress and caspase 3/7 activation. The release of cathepsin L and B were also observed with PA treatments. However, in hyperglycemic SCs, PA-LTx induced- ER stress followed mitochondrial injury, oxidative stress, caspase 3/7 activation with a subsequent xviii lysosomal release of cathepsins. Of interest is the observation that hyperglycemia was able to magnify SC injury resulting in an earlier and more severe cell death. Treatment of iSC cultures with the calcium chelator BAPTA-AM resulted in an increase in cell viability in iSC cultures. In addition, treatment with antioxidant MCI-186 reduced oxidative stress and increased cell viability in both euglycemic and hyperglycemic SC exposed to PA. Furthermore, PA-LTx was able to disrupt mRNA and protein levels of Peripheral Myelin protein 22 within the first 12hrs. Understanding the mechanism of lipotoxicity is of importance in order to bring innovative therapies to ameliorate debilitating conditions such as diabetic neuropathy.

LLU Discipline

Anatomy

Department

Pathology and Human Anatomy

School

School of Medicine

First Advisor

Marino De Leon

Second Advisor

Carlos A. Casiano

Third Advisor

Michael Kirby

Fourth Advisor

William Langridge

Fifth Advisor

Kimberly Payne

Degree Name

Doctor of Philosophy (Medical Science)

Degree Level

Ph.D.

Year Degree Awarded

2011

Date (Title Page)

12-2011

Language

English

Library of Congress/MESH Subject Headings

Lipid Metabolism; Hyperlipidermias -- pathology; Hyperlipidermias -- physiopathology; Hyperlipidermias -- metabolism; Lipotropic Agents -- metabolism; Palmitic Acid -- metabolism; Palmitic Acid -- toxicity; Schwann Cells -- pathology; Schwann Cells -- metabolism; Schwann Cells -- drug effects; Cells, Cultured; Cell Aging -- physiology; Cell Aging -- drug effects; Diabetic Neuropathies -- pathology; Diabetic Neuropathies -- physiopathology; Diabetic Neuropathies -- metabolism; Hyperglycemia -- pathology; Hyperglycemia -- physiopathology; Hyperglycemia -- metabolism; Academic theses

Type

Dissertation

Page Count

226 p.

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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