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Author ORCID Identifier

https://orcid.org/0000-0002-4157-2481

Date Available

3-24-2026

Year of Publication

2026

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Medicine

Department/School/Program

Pharmacology and Nutritional Sciences

Faculty

Terry D. Hinds, Jr

Faculty

Gang Chen

Abstract

Metabolic homeostasis is maintained through tightly coordinated signaling networks that integrate diverse physiological inputs. Central to this regulation are transcription factors, which sense nutrient, hormonal, and vitamin-derived signals and translate them into coordinated gene expression programs. Transcription factor activity is governed by DNA binding, recruitment of coregulatory proteins, and interactions with specific response elements in gene promoters, which allows them to selectively modulate diverse metabolic pathways. Owing to their multifactorial and tunable nature, transcription factors have emerged as promising targets for the treatment and diagnosis of metabolic diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). This dissertation explores the molecular mechanisms by which nutrients stimulate transcription factors to bind DNA, and their signaling mechanisms in metabolic disease. First, it provides a comprehensive review of nutrient-driven transcriptional regulation, focusing on nutrients acting as signaling agents. Next, it examines how regulatory proteins shape nuclear receptor signaling in a sex- and disease-specific manner and highlights new technologies that can detect these dynamic changes in coregulator recruitment. Building on this mechanistic framework, we demonstrate the translational potential of transcription factor targeting by increasing plasma bilirubin, an established ligand for peroxisome proliferator activated receptor alpha (PPARa), using siRNA-based approaches, resulting in improved metabolic outcomes without adverse effects. Finally, we identify Forkhead Box S1 (FOXS1) as a cell-type specific biomarker associated with the progression of MASLD to fibrosis. Collectively, these studies establish transcription factors and their regulatory networks as central drivers of metabolic signaling and underscore their utility as precision targets for the diagnosis, detection, and treatment of metabolic disease.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2026.22

Archival?

Archival

Funding Information

This work was supported by the National Institutes of Health (NIH) grants R01DK121797, R01DA058933, R01HL174521, F31HL170972, and F31HL175979, and a fellowship award from the America Heart Association (AHA) for 25PRE1374495. 

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