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Access Type
WSU Access
Date of Award
January 2024
Degree Type
Thesis
Degree Name
M.S.
Department
Pharmaceutical Sciences
First Advisor
Wanqing Liu
Abstract
The PNPLA3 148I>M variant is associated with non-alcoholic fatty liver disease (NAFLD) and its advanced-form non-alcoholic steatohepatitis (NASH). However, the detailed mechanism underlying this association remains incompletely understood. This study aims to further explore the molecular pathogenic mechanism of PNPLA3-148M-driven NASH via an integrated metabolomic and transcriptomic analysis in a humanized PNPLA3 mouse model. Transgenic mice carrying the human PNPLA3-148I or PNPLA3-148M gene isoform were fed a NASH-inducing AMLN diet for 20 weeks. Metabolomic analyses were conducted for the liver tissue and serum samples, and the transcriptome of the liver tissue was also analyzed via RNA-seq. A total of 843 and 774 metabolites were profiled in mouse liver and serum samples, respectively. In the liver, levels of 101 metabolites were found to be significantly changed in the PNPLA3-148M group compared to the PNPLA3-148I mice (p<0.05). In the serum, there were 109 metabolites found to be significantly changed between the two groups (p<0.05), with most of those metabolites being free fatty acids and intermediate metabolites of the fatty acid metabolism. Enrichment analysis revealed that pathways including folate metabolism, choline metabolism, citric acid cycle, glutamate metabolism, and methionine metabolism in the liver and lipids metabolism pathways in the serum were significantly different between the two strains. In a detailed analysis, PNPLA3-148M mice possesses a significant shift in energy production from glycolysis and lipogenesis to FAO and amino acids metabolism, which may promote ketogenesis. These alterations in energy production and conversion parallel a significant remodeling of lipids distribution including accumulation of cholesterol, sphingomyelins and ceramides, as well as PUFA retention in the PC fraction. Meanwhile, the active FAO may lead to an overproduction of reactive oxygen species, increasing mitochondria stress. Lastly, we observed a significant change in choline metabolism and distribution in the PNPLA3-148M mice, leading to an impaired production of glutathione and a decreased ratio of S-Adenosylmethionine and S-adenosylhomocysteine (SAM/SAH), as well as a genome-wide hypermethylation. Our study confirmed many metabolic changes associated with the PNPLA3-148M variant among both humans and multiple models in vitro and in vivo, and observed new changes in choline metabolism and DNA hypermethylation. Our findings provide further evidence to understand the mechanism underlying which PNPLA3-148M promotes the development and progression of NAFLD.
Recommended Citation
Peng, Zheyun, "Pnpla3-148m Is Associated With Metabolic Remodeling In The Progression Of Non-Alcoholic Fatty Liver Disease" (2024). Wayne State University Theses. 954.
https://digitalcommons.wayne.edu/oa_theses/954