Amino Acid Restriction Triggers Angiogenesis via GCN2/ATF4 Regulation of VEGF and H2S Production

Molecular Nutrition Food Res

Yang

et al. 2018

Scope Dietary methionine restriction (MR) promotes multifaceted health benefits. Moreover, lower rate of protein synthesis by dietary MR is associated with life span extension. The goal of this work is to explore how dietary MR would affect protein metabolism in a mouse model of high‐fat‐diet‐induced obesity (DIO). Methods and results DIO mice (male C57BL/6) are subjected to dietary MR for 22 weeks. High‐throughput sequencing technology, qRT‐PCR analysis, and the dual luciferase reporter assay are performed to verify that MiR‐328‐3p directly targets cystathionine γ‐lyase (CSE) to modulate endogenous H2S production. Moreover, indicators of endogenous H2S, fractional synthesis rate (FSR), fractional growth rate (FGR), fractional degradation rate (FDR), and protein retention efficiency (PRE) are analyzed. MR results in an increase in endogenous H2S to relieve oxidative stress and ER stress to improve protein homeostasis and metabolic efficiency in DIO mice. Conclusion Results show that dietary MR increases endogenous H2S production via miR‐328‐3p. Furthermore, these results suggest the potential involvement of endogenous H2S on the efficiency of protein metabolism in dietary MR.

Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 82%

Dietary Methionine Restriction Upregulates Endogenous H₂S via miR‐328‐3p: A Potential Mechanism to Improve Liver Protein Metabolism Efficiency in a Mouse Model of High‐fat‐diet‐induced Obesity

Molecular Nutrition Food Res

Yang

et al. 2018

“…In the current study, we examined the multi-tissue and systemic extent to which dietary restriction (DR), a well-studied anti-aging intervention (Fontana and Partridge, 2015), impacts H2S production capacity and the sulfhydromes in liver, kidney, muscle, brain, heart, and plasma. In addition, we hypothesized the H2S producing enzyme cystathionine γ-lyase (CGL), which is required for stress resistance and angiogenesis benefits of shortterm DR (Hine et al, 2015;Longchamp et al, 2018;Trocha et al, 2019), is partially required for baseline and diet-induced changes in tissue-specific sulfhydromes. We found H2S production is strongest in liver and kidney and primarily driven by CGL in these tissues, while other tissues had relatively weak H2S production independent of CGL.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to their differences in subcellular localization, CGL, CBS, and 3-MST are differentially expressed and active in tissue-specific manners, with CGL contributing the majority of enzymatic H2S production in the kidney, liver, and endothelium (Kabil et al, 2011b;Longchamp et al, 2018;Yang et al, 2019). Lack of CGL expression and/or activity is attributed to hypertension (Yang et al, 2008), neurodegeneration (Paul et al, 2014), and the inability to properly respond to dietary and endocrine cues (Hine et al, 2015;Ishii et al, 2010;Kabil et al, 2011a;Longchamp et al, 2018;Nakano et al, 2015). Remarkably, it was recently found that increased CGL expression in liver is a hallmark of numerous dietary, genetic, hormonal, and pharmaceutical mouse models of extended lifespan and may serve as a molecular biomarker associated with longevity (Tyshkovskiy et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Dietary restriction transforms the protein sulfhydrome in a tissue-specific and cystathionine γ-lyase-dependent manner

Bithi

Link

et al. 2019

Preprint

Self Cite

One Sentence Summary: Dietary restriction altered the tissue-specific enrichment of sulfhydrated proteins and their downstream signaling pathways in liver, kidney, skeletal muscle, brain, heart, and plasma that was partly dependent on the hydrogen sulfide producing enzyme cystathionine γ-lyase.Abstract: Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein sulfhydration (R-SSnH). Despite the known importance of sulfhydration on relatively few identified proteins, tissue-specific sulfhydrome profiles and their associated functions are not well characterized, specifically under conditions known to modulate H2S production. We hypothesized that dietary restriction (DR), which increases lifespan and boosts endogenous H2S production, expands functional tissue-specific sulfhydromes. Here, we found that 50% DR enriched total sulfhydrated proteins in liver, kidney, muscle, and brain but decreased these in heart of adult male mice. DR promoted sulfhydration in numerous metabolic and aging-related pathways. Mice lacking the H2S producing enzyme cystathionine γ-lyase (CGL) had decreased liver and kidney protein sulfhydration and failed to functionally augment their sulfhydrome in response to DR. Overall, we defined tissue-and CGLdependent sulfhydromes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health.

“…In the nutrition restriction or hypoxia conditions, one adaptive response is the formation of new blood vessels, which is termed as angiogenesis. A recent study found that the GCN2/ATF4 pathway regulates VEGF expression and angiogenesis upon SAA (sulfur amino acid) restriction in endothelial cells, and this process is independent of hypoxia or HIF1α (hypoxia-induced factor 1α) (Longchamp et al 2018). In addition to sensing signal amino acid deprivation, TORC1 and GCN2 respond to different dietary protein sources.…”

Section: Gcn2 a Master Regulator Of Amino Acid Restrictionmentioning

confidence: 99%

Recent advances in amino acid sensing and new challenges for protein nutrition in aquaculture

Liu

Zhou

et al. 2019

Mar Life Sci Technol

From the conventional knowledge of protein nutrition to the molecular nutrition of amino acids, our understanding of protein/ amino acid nutrition is rapidly increasing. Amino acids control cell growth and metabolism through two amino acid-sensing pathways, i.e. target of rapamycin complex 1 (TORC1) and the general control nonderepressible 2 (GCN2) signaling pathway. In the amino acid-abundant status, TORC1 dominates intracellular signaling and increases protein synthesis and cell growth. In contrast, amino acid deprivation actives GCN2 resulting in repression of general protein synthesis but facilitates the amino acid transport and synthesis process. By integrating and coordinating nutrition and hormone signaling, TORC1 and GCN2 control the switch of the catabolism and anabolism phase in most eukaryotes. Now, we appreciate that the availability of individual amino acids is sensed by intracellular sensors. These cutting-edge findings expand our knowledge of amino acid nutrition. Although the TORC1 and GCN2 were discovered decades ago, the study of molecular amino acid nutrition in aquaculture animals is still at its infancy. The aquaculture industry is highly dependent on the supply of fishmeal, which is the major protein source in aquacultural animal diets. Some concerted efforts were conducted to substitute for fishmeal due to limited supply of it. However, the concomitant issues including the unbalanced amino acid profile of alternative protein sources limited the utilization of those proteins. Continued study of the molecular nutrition of amino acid in aquaculture animals may be expected in the immediate future to expand our knowledge on the utilization of alternative protein sources.Keywords Molecular nutrition · Amino acid sensor · GCN2 · TORC1 · Aquaculture · Fishmeal replacement TORC1, the center of amino acid-dependent signaling for growth and metabolismAs fundamental elements for the growth of all organisms, the input of protein/amino acid initiated a series of subcellular responses. However, the mechanisms by which amino