Metabolism of omega-3 endocannabinoids by cytochrome P450s and the role of their metabolites in neurodegenerative diseases

There has been growing interest in unveiling the mechanisms by which nutritional status influences the immune response, especially related to the consumption of omega-3 fatty acids. Cytochrome P450 (CYP) epoxygenases are versatile heme-containing enzymes capable of metabolizing xenobiotics, sterols, fatty acids, eicosanoids, and vitamins. The omega-3 and omega-6 fatty acid metabolizing CYPs produce anti-inflammatory and immunomodulatory lipid mediators. Furthermore, lipids also serve as a key structural component for biological function. Therefore, the research in this dissertation focuses on three major areas: 1) unveiling the biological properties of omega-3 endocannabinoid lipid mediators with respect to T-cell activity in a multiple sclerosis animal model, 2) identifying how CYP-mediated metabolism can be influenced by xenobiotics, and 3) unraveling the potential role of structural lipids in ensuring homeostatic function in neurodegenerative conditions induced by influenza virus. hapter 2 is the investigation of the immunomodulatory capability endocannabinoids possess in inflammatory and neurodegenerative diseases such as multiple sclerosis. While epidemiological studies correlated dietary intake of omega-3 fatty acids such as docosahexaenoic acid (DHA) with improved quality of life in multiple sclerosis (MS), the precise mechanism is not well understood. As DHA can be endogenously metabolized to form endocannabinoid lipid mediators, the goal of this study was to identify how endocannabinoids can modulate neuroinflammatory responses in a preclinical model of MS. In this study, we discovered that docosapentaenoyl ethanolamine (DHEA) and epoxydocosapentaenoyl ethanolamine reduces Th1 and Th17 polarization, both of which contribute to the pathogenesis of MS. In a preclinical animal model of MS, we discover that DHEA delays the disease onset, time to relapse, and the overall percentage of infiltrating CD4+ T-cells in the central nervous system. Collectively, we identify the relationship of endocannabinoids and CD4+ T-cells in a neuroinflammatory disease model. In Chapter 3, we explore how Cytochrome P450 2J2 (CYP2J2) mediated metabolism of arachidonic acid to form cardioprotective endocannabinoid epoxyeicosatrienoic acids can be influenced by xenobiotics. Specifically, anthracycline chemotherapeutics are highly effective, but their clinical usefulness is hindered by adverse side effects such as cardiotoxicity. As CYP2J2 is expressed in the heart and can convert arachidonic acid to cardioprotective epoxyeicosatrienoic acid (EET) regioisomers, we performed biochemical studies to understand the interaction of anthracycline derivatives with CYP2J2. Through biochemical assays and iterative ensemble docking, we unveil the interactions of anthracycline derivatives with CYP2J2. Collectively, these studies will help identify alternative mechanisms of how anthracycline cardiotoxicity may be mediated through the inhibition of cardiac P450, and broadly provides insight into how endocannabinoid production can be influenced by xenobiotics. In Chapter 4, we explore the role of lipids as structural components in the myelin. The notion that myelin remains static during adulthood has been challenged in recent years, and is crucial for proper cognitive function, behavior, and can be influenced by external factors. As peripheral infection and subsequent systemic inflammation can exacerbate neurological diseases, we explore how an upper respiratory infection can alter the myelin lipidome in an animal model. In this study, we infect C57BL/6 mice with mouse-adapted human influenza A virus and isolate the myelin from the brain. Using a shotgun lipidomic approach, we determine that a majority of lipid classes with the exception of sphingosine and triglycerides increase as a result of infection. Importantly, we identify those lipids that are differentially expressed belong to the glycerophospholipid and sphingolipid signaling pathways. As these lipids play a critical role in the structural integrity of myelin, we identify how upper respiratory infection can cause changes to the biochemical and anatomical characteristics of myelin. In summary, our work presented in this dissertation advances our understanding of the role of structural lipids and lipid mediators in the larger context of neurodegenerative and autoimmune disease states.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Nutritional Sciences

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2022

Author dc:creator

• Kim, Justin Sehyun

Contributors dc:contributor

• Das, Aditi
• Steelman, Andrew J
• Johnson, Rodney
• Gaskins, Rex H

• ENDOCANNABINOID
• CYTOCHROME P450
• MULTIPLE SCLEROSIS
• INFECTION

Statement dc:rights

• Copyright 2022 Justin S. Kim

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/115914

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F115914