DOI
https://doi.org/10.25772/1GQ8-CP96
Defense Date
2025
Document Type
Thesis
Degree Name
Master of Science
Department
Human and Molecular Genetics
First Advisor
Christopher Green
Abstract
Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) is characterized by excessive fat accumulation in the liver, with metabolic dysfunction-associated steatohepatitis (MASH) representing a more severe form that can progress to cirrhosis or hepatocellular carcinoma (HCC). The sphingosine kinases and the S1P signaling pathway are key regulators of MASH and HCC progression. While much is known about the mechanisms contributing to MASH-HCC in males, less is known for females. Nevertheless, we previously identified sphingosine Kinase 2 (SphK2) to protect females from MASH-driven HCC. This study first performed differential gene expression analysis on human liver cohorts to examine sex-specific differences in gene expression between males and females and their corresponding canonical pathways. Notably, comparing MASH to MAFL patients found many key characteristics of MASH similarly regulated in both sexes for Cohort 1, whereas protein translation and metabolism were reduced in males. In addition, analysis of Cohort 3 patients with low and high risk of HCC identified high-risk females to exhibit impaired mitochondrial RNA processing. Next, differential expression analysis was performed for female wild-type (WT) and SphK2 knockout (KO) mice from our MASH-HCC model. Comparing Cohort 3 with the mice cohort revealed four upregulated genes in high-risk females and SphK2 KO mice, all of which are associated with poorer survival in liver cancer patients. Overall, this study identified genes and pathways potentially contributing to sex-specific differences in human MASH and MASH-associated HCC, and further revealed genes upregulated in both high-risk females and SphK2 KO mice linked to poorer survival in liver cancer.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
4-30-2025