Author ORCID Identifier

https://orcid.org/0009-0000-2212-386X

Semester

Spring

Date of Graduation

2026

Document Type

Thesis

Degree Type

MS

College

School of Medicine

Department

Exercise Physiology

Committee Chair

Paul D. Chantler

Committee Member

Randall Bryner

Committee Member

Dharendra Thapa

Abstract

Background: Approximately 1 billion people currently live with obesity. Driven by factors such as a high-fat diet (HFD), this pathology can have drastic effects throughout the body, with the liver in particular being a main target of its downstream consequences. Although it is capable of storing lipids, excess fat can conglomerate in the liver and contribute to various hepatic pathologies. A specific pattern of hepatic dysfunction seen in response to an HFD is increased acetylation of mitochondrial proteins. Further, expression and activity of insulin-degrading enzyme (IDE), involved in the degradation of Aβ, are altered in response to an HFD. Aβ is a protein thought to drive much of the dysfunction characteristic of Alzheimer’s disease, which, together with other types of dementia, are the seventh leading cause of death worldwide. HFD-driven acetylation of IDE has not been studied but could lead to decreased hepatic enzyme activity and downstream accumulation of Aβ in the brain, thereby posing a possible link between obesity and cognitive decline.

Methods: We administered both a 60% high-fat diet and 10% low-fat diet to male and female 3xTg-AD mice and their genetic controls from weaning until euthanasia at nine months. We performed various histological analyses in the liver in addition to quantifying hepatic protein and acetylation levels via Western blotting and immunoprecipitation pulldowns, respectively. Additionally, we quantified hepatic IDE activity and the downstream accumulation of Aβ in the brain.

Results: No diet-based differences were observed in global acetylation levels; IDE levels, acetylation, or activity; or cortical Aβ levels. However, we did observe specific sex-dependent hepatic phenotypes in response to the 3xTg mutation, as well as a significant decrease in hepatic IDE activity in 3xTg animals. We also found correlations, albeit relatively weak, between hepatic IDE activity and both hepatic IDE acetylation (negative correlation) and cortical Aβ levels (positive correlation).

Conclusion: Together, our results do not support HFD-induced acetylation changes as a driver of hepatic dysfunction in response to an HFD. However, we propose the need for further investigation into the effect of an HFD on IDE acetylation, particularly in relation to its functional capacity to clear brain-derived Aβ.

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