Unraveling the interplay between amino acid and lipid metabolism in disease and its impact on tissue physiology
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Unraveling the interplay between amino acid and lipid metabolism in disease and its impact on tissue physiology

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Altered metabolism is a hallmark of aging and diseases such as cancer, diabetes, and neuro-retinal disorders. These alterations are often multi-faceted and encompass a reprogramming of multiple metabolic networks that make understanding these changes challenging. As such, while the role of metabolism in driving disease phenotypes is clear, many of the mechanisms involved are still not well understood. Within the metabolic network, amino acids and lipids are two important and related bioactive metabolite classes that have critical roles in cellular function and homeostasis. In this dissertation, we study the interplay between amino acid and lipid metabolism in the context of aging and disease. First, we comprehensively quantified the metabolic alterations and fluxes in PolgD257A mice, a mouse model of mitochondrial dysfunction, over time and compared them to age-matched wild-type (WT) controls. By linking mitochondrial dysfunction to alanine and non-canonical 1-deoxysphingolipid (doxSL) accumulation, we highlight a distinct mechanism through which mitochondrial defects can drive the accumulation of toxic lipids which result in thermal hypoalgesia. Next, we modulate amino acid metabolism through dietary intervention in C57BL/6J mice. By feeding C57BL/6J mice serine- and glycine-free diets, we were able to model the systemic serine and glycine deficiency observed in patients with macular telangiectasia type 2 (MacTel), a progressive retinal degenerative disease. We show that the retina relies on multiple mechanisms to maintain serine homeostasis. Importantly, we demonstrate the efficacy of dietary serine supplementation to reverse retinal and peripheral neuropathy defects in mice through the restoration of serine levels and suppression of doxSLs. Finally, we study how serine deficiency compromises lipid synthesis and processing as altered serine and glycine metabolism have been linked to metabolic disorders. Here, we show that serine/glycine deficiency differentially impacts lipid metabolism in the liver, intestine, and adipose tissue. Together, the results highlight the distinct mechanisms in which mitochondrial dysfunction or chronic nutrient stress can perturb amino acid metabolism and impact lipid processing which can drive age-associated phenotypes. By connecting these metabolic changes to specific phenotypes such as peripheral neuropathy, retinal defects, and adiposity, this work also provides potential therapeutic strategies for treatment of these disorders.

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This item is under embargo until April 24, 2025.