Date of Award

Winter 12-3-2021

Degree Type

Dissertation

Degree Name

PhD Molecular Bioscience

Department

Biology

Advisor

Heping Zhou, Ph.D.

Committee Member

Edward G. Tall, Ph.D.

Committee Member

Sylvia Rabacchi, Ph.D.

Committee Member

Angela Klaus, Ph.D.

Committee Member

Vladislav Snitsarev, Ph.D.

Keywords

Lipotoxicity, Lipoprotection, Palmitate, Saturated fatty acid, Unsaturated fatty acid

Abstract

Nearly three-in-four Americans are overweight or obese. Obesity has long been recognized as a risk factor for several diseases. Obesogenic diseases often present comorbidly and include dyslipidemia, diabetes mellitus, cardiovascular disease, non-alcoholic fatty liver disease, dementia, chronic inflammation, and others, which collectively constitute the features of metabolic syndrome. Obese individuals and metabolic syndrome patients display elevated levels of fatty acids in their blood sera and cerebrospinal fluid which has been mechanistically linked to several obesogenic diseases. Saturated fatty acid overload is generally toxic to non-adipose tissues; palmitate (PA), the most abundant saturated fatty acid in human sera, is pathologically elevated in obese individuals. While lipotoxicity has been well studied in peripheral tissues, less is known about the lipotoxic effects of elevated PA within the brain. This dissertation presents a series of studies which were designed to systematically characterize lipotoxicity in neuronal and microglial cells, revealing contrasts between lipotoxic manifestation in these cell types and a novel feature of lipotoxicity in neuronal cells; to examine the role and mechanisms of fatty acid uptake in lipotoxicity, revealing that PA promotes a positive feedback-like effect on its own uptake which requires CD36 for lipotoxicity in neuronal cells; to interrogate mechanisms of unsaturated fatty acid (UFA)-mediated lipoprotection against PA lipotoxicity, revealing that UFAs inhibit SFA uptake and differentially direct fatty acid metabolic utilization in neuronal and microglial cells; to identify signaling pathways mediating PA lipotoxicity, revealing that CD36-dependent modulation of Akt and AMPK signaling mediates early events of PA lipotoxicity in neuronal cells. Together, these studies shed light on the molecular mechanisms of lipotoxicity within the brain, and may provide useful insights for the development of novel therapeutic strategies.

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