DOI
https://doi.org/10.25772/B5Q5-9612
Author ORCID Identifier
https://orcid.org/0000-0003-2663-9593
Defense Date
2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Microbiology & Immunology
First Advisor
Huiping Zhou
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) currently affects one in three people worldwide; its prevalence is growing alongside other cardiometabolic disorders. Aberrations to redox and sphingolipid metabolism contribute to MASLD pathologic progression. Sphingosine-1-phosphate (S1P) is an active lipid, meaning that S1P participates in biochemical processes within the cell. S1P is generated by two distinct isoenzymes, sphingosine kinase (SphK)1 and SphK2. The localization of the SphK enzyme dictates S1P function. While cytosolic SphK1-generated S1P is well-characterized, nuclear and mitochondrial SphK2-generated S1P is less known. Moreover, SphK2 depletion effects on cellular redox processes and inflammation are not well-defined.
This study defines the functional outcomes of SphK2 depletion on inflammation and hepatic redox metabolism, focusing on mitochondrial dysfunction and proinflammatory mediator production that leads to immune recruitment in early MASH. Utilizing a 16-week Western diet and sugar water- (WDSW)-induced mouse model of early MASH, WDSW-SphK2-/- mice exhibit distinct expression changes to multiple metabolism-associated genes, increased microvesicular steatosis, increased mitochondrial cholesterol and S1P metabolic precursors, and decreased mitochondrial oxidative phosphorylation. Rather than exhibiting a pronounced effect on specific metabolic pathways at the transcriptional level, WDSW-SphK2-/-mice incur significant increases in proinflammatory responses, including increased transcriptional expression for genes encoding cytokine and chemokines, oxylipin formation, and immune infiltrate compared to WDSW-WT mice. Our findings provide novel insights into SphK2 as a key enzyme whose reduction or knockout may exacerbate mitochondrial dysfunction and inflammation in MASH. These data also highlight the need for continued studies to examine the functional outcomes and mechanisms associated with SphK2 in specific cell subsets and to explore sphingolipid therapeutic targeting as a potential treatment for MASLD.
Rights
© Kaitlyn G. Jackson
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
11-19-2024
Included in
Cell Biology Commons, Cellular and Molecular Physiology Commons, Immunopathology Commons, Molecular Biology Commons, Molecular, Genetic, and Biochemical Nutrition Commons