Year: 2025
Type: dissertation
Abstract: Metabolism is a foundational driver of life, deeply conserved through evolution to support survival. Yet in the context of modern environmental and dietary pressures, these once-adaptive systems are increasingly implicated in the onset and progression of chronic diseases. This dissertation investigates how metabolic regulation and its dysregulation shapes disease susceptibility and progression—providing avenues for prevention, diagnosis, and treatment.In these studies, my colleagues and I dissect dysfunctional metabolism through a combination of metabolomics, lipidomics, isotope tracing, and in-vivo genetic mouse modeling. This work uncovers context-specific metabolic adaptations across diverse disease settings of the liver and kidney. Further, evolutionary insights into metabolic compartmentalization that help explain the systemic impact of organ-specific dysfunction are discussed—emphasizing the role genetics and diet in metabolic diseases of the liver and kidney in the first chapter. In the second chapter, we identify circulating glycerate as a predictive biomarker of resistance to fructose-induced steatosis, emphasizing the small intestine's protective role and laying the groundwork for personalized dietary strategies. In the third chapter, we reveal how liver tumors escape ferroptosis by elongating polyunsaturated fatty acids via ELOVL2—a vulnerability that can be therapeutically targeted. Lastly, in the fourth chapter, we demonstrate that TSC-mutated kidney tumors accumulate essential amino acids likely through enhanced protein degradation rather than uptake from circulation, offering a new angle to disrupt mTORC1-fueled tumor growth. Together, these findings highlight metabolism not only as a universal requirement of life, but as a dynamic, targetable system in disease. In the concluding fifth chapter I raise broader questions about how medicine currently addresses metabolic dysfunction in patients. Highlighting how the healthcare systems prioritize symptom management and underscoring the urgency of shifting toward prevention, early detection, and science-informed policymaking. The ultimate goal being to bridge scientific insight with clinical application, improving outcomes for today’s patients while informing strategies to prevent disease in generations to come.
Author: Ramirez, Cuauhtemoc Blas
Institution: University of California, Irvine
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7064581098