Dietary amino acid restriction and the integrated stress response
Creators: name: Jonsson, William O.
Publisher: name: No Publisher Supplied
Year: 2022

description: Dietary amino acid restriction produces beneficial health effects in a range of experimental animal models and is characterized by an overall reduction in growth and extension of both lifespan and healthspan. However, a significant portion of the mechanistic understanding of how dietary amino acid restriction exerts its effects remain to be detailed.One of the major networks responding to cellular amino acid restriction is the integrated stress response (ISR). The prevailing contemporary understanding of the ISR dictates that various forms of amino acid restriction are all transmitted through the ISR via two kinases, general control nonderepressible 2 (GCN2) or PKR-like ER kinase (PERK), through eukaryotic initiation factor 2 (eIF2) to activating transcription factor 4 (ATF4). This canonical ISR exerts translational control to ultimately induce transcriptional realignment aimed at alleviating perceived amino acid stress. Notably, insights into how the ISR regulates and fine tunes these responses are in large part derived from in vitro studies, rather than from studies in whole animals. Hence, the objective of this dissertation was to detail the role of the ISR during different forms and levels of dietary amino acid restriction in whole animals and was addressed in three major mouse studies focusing on liver.The first study addressed the role of ATF4 during dietary sulfur amino acid (SAA) restriction (SAAR). It was found that ATF4 was dispensable in the chronic induction of the hepatokine fibroblast growth factor 21, while being essential for the sustained production of endogenous hydrogen sulfide, both central in healthspan modulation. This study also affirmed that biological sex, independent of ATF4 status, was a determinant of the response to dietary SAAR.A second study surveyed how SAAR on different dietary fat backgrounds altered liver protein synthesis at the level of individual proteins. Dietary SAAR changed the hepatic ribo-interactome regardless of dietary fat, altering synthesis rates of ribosomal proteins, molecular chaperones and other components of the translational machinery. Furthermore, the liver leveraged differential strategies to maintain hepatic redox status during SAAR when fed different dietary fat levels. These potential adjustments in translation, folding and redox capacity coupled with a reduction in bulk client load might serve to bolster the ability to maintain proteostasis, thereby exerting cytoprotective effects in liver through improved translational fidelity.A third and final study explored amino acid-specific patterns in translational control in liver. Comparing the acute translational response to either a leucine devoid or a SAA devoid diet in both wild-type and Gcn2 knockout mice, this study found that leucine deprivation evoked a greater essential amino acid imbalance compared to SAA deprivation, activating the ISR to a greater extent. Nonetheless, in both dietary conditions, liver tRNA levels remained similar to levels in mice fed a complete diet. On a global scale, lack of GCN2 increased occurrence of ribosome collisions in liver. Translational output was consequential to mRNA abundance and required GCN2 during leucine deprivation but not sulfur amino acid deprivation. These observations illustrate the existence of multiple amino acid-specific mechanisms of translational control in liver during dietary amino acid insufficiency.The data within this dissertation provides several insights into the complex mechanisms that govern the response to dietary amino acid restriction in mouse liver. It highlights the many ways in which the ISR can be tailored and adapted to a given nutritional context and biological setting.