Date of Award

Spring 5-20-2023

Embargo Period

4-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cell and Molecular Pharmacology and Experimental Therapeutics

College

College of Graduate Studies

First Advisor

Anand Mehta

Abstract

The high mortality rates of liver diseases and primary liver cancers can be attributed to the lack of screening and diagnostic strategies currently available for early detection. Non-alcoholic fatty liver disease (NAFLD) is an early stage of liver disease known to progress to a variety of pre-malignant and malignant conditions, like advanced fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and cholangiocarcinoma (CCA). Based on the wide variety of diseases that NAFLD can progress to, strategies to understand and detect the progression of NAFLD are of great value. Core fucosylation of N-linked glycans has been demonstrated to be useful for the clinical diagnosis of HCC, through the use of the serum biomarker AFP-L3. However, the role of core fucosylation, catalyzed by Fucosyltransferase (Fut8) in HCC or any liver diseases is still not fully understood. Here, we utilized human samples and an in vivo approach to characterize the origin, temporal changes, and biomarker use of modifications in N-liked glycosylation by MALDI-IMS (Matrix-assisted laser desorption/ionization imaging mass spectrometry) in NAFLD and its progressive form. Spatial N-glycan analysis in NAFLD mouse and human liver biopsies revealed that fucosylated N-linked glycan modifications correlate with areas of fibrosis. Next, we use an in vivo liver disease induction time point study to elucidate that bisected fucosylated N-glycan modifications can be observed even before histopathological alterations are significant and are consistently altered from fatty liver disease, up to stages with liver dysplasia. For CCA, we took a biomarker discovery approach in tissue and serum and identified that bisected fucosylated structures distinguished CCA patients from those with any other type of liver disease and normal tissue, better than the gold-standard serum biomarker for CCA, CA-19-9. Finally, we generated the first liver specific Fut8 mouse model to further study the impact of core fucosylation in these liver diseases. Overall, the studies presented in this dissertation, elucidate the value of N-glycosylation for biomarker strategies for early detection and different stages of progressive liver disease. Importantly, these studies set the field for a mechanistic approach to one of the most characterized N-glycan modifications in liver cancer by the generation of a tissue-specific mouse model.

Rights

Copyright is held by the author. All rights reserved.

Download

Share

COinS