Deoxyhypusine synthase promotes a pro-inflammatory macrophage phenotype

Anderson-Baucum, Emily; Piñeros, Annie R.; Kulkarni, Abhishek; Webb‐Robertson, Bobbie‐Jo; Maier, Bernhard; Anderson, Ryan M.; Wu, Wenting; Tersey, Sarah A.; Mastracci, Teresa L.; Casimiro, Isabel; Scheuner, Donalyn; Metz, Thomas O.; Nakayasu, Ernesto; Evans‐Molina, Carmella; Mirmira, Raghavendra G.

doi:10.1016/j.cmet.2021.08.003

Cited by 39 publications

(29 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our study, we subjected zebrafish larvae to a “two-hit” paradigm, wherein they were first fed a lipid-rich diet to excess, followed by induction of cytokines using our Liver-CETI-PIC3 system. We studied macrophage infiltration using the Tg(mpeg:GFP) line that we have well-characterized for studying migration and infiltration of these immune cells in other inflammation models [ 36 , 37 ]. Curiously, while the animals subjected to the HFD alone exhibited a clear inflammatory response, those only mis-expressing cytokines hepatically via Li-PIC3 did not.…”

Section: Discussionmentioning

confidence: 99%

A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease

et al. 2022

Self Cite

View full text Add to dashboard Cite

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in adults. NAFLD progresses from benign liver fat accumulation to liver inflammation and cirrhosis, and ultimately leads to liver failure. Although several rodent models have been established for studying NAFLD, they have limitations that include cost, speed of disease development, key dissimilarities, and poor amenability to pharmacological screens. Here, we present a novel 2-hit zebrafish model to replicate aspects of NAFLD pathogenesis. We fed zebrafish larvae a high-fat diet (HFD) to drive liver fat accumulation (first hit). Next, we exacerbated liver-specific inflammation using a transgenic line (fabp10-CETI-PIC3) that induces the expression of proinflammatory cytokines following induction with doxycycline (second hit). These hits promoted fat accumulation and liver inflammation, as demonstrated by the high expression of inflammatory cytokines, macrophage infiltration, stress induction, and hepatic lipid droplet accumulation. Furthermore, zebrafish in this paradigm showed deranged glucose metabolism. To validate a small-molecule screening approach, we treated HFD-fed fish with pioglitazone, a drug shown to be beneficial for NAFLD in humans, and measured a sharp reduction in liver lipid accumulation. These results demonstrate new utility for zebrafish in modeling early NAFLD pathogenesis and demonstrate their feasibility for in vivo screening of new pharmacological interventions.

show abstract

Section: Discussionmentioning

confidence: 99%

A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…eIF5A is the only protein known to be posttranslationally modified via hypusination: (1) deoxyhypusine synthase (DHPS) transfers the 4-aminobutyl group derived from spermidine to the eIF5A Lys50-deoxyhypusine ; (2) deoxyhypusine hydroxylase (DOHH) catalyzes the hydroxylation to generate eIF5A hyp . Since global deletion of Dhps is embryonic lethal in mice, cell-type-specific deletions are required [16]. Puleston et al generated Dohh-∆T and Dhps-∆T mice to specifically delete DOHH and DHPS, respectively, in CD4+ T cells [13].…”

Section: Deficiency In Polyamine Biosynthesis In Cd4+ T Cells Confers...mentioning

confidence: 99%

Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses

et al. 2022

View full text Add to dashboard Cite

Polyamine biosynthesis is frequently dysregulated in cancers, and enhanced flux increases intracellular polyamines necessary for promoting cell growth, proliferation, and function. Polyamine depletion strategies demonstrate efficacy in reducing tumor growth and increasing survival in animal models of cancer; however, mechanistically, the cell-intrinsic and cell-extrinsic alterations within the tumor microenvironment underlying positive treatment outcomes are not well understood. Recently, investigators have demonstrated that co-targeting polyamine biosynthesis and transport alters the immune landscape. Although the polyamine synthesis-targeting drug 2-difluoromethylornithine (DFMO) is well tolerated in humans and is FDA-approved for African trypanosomiasis, its clinical benefit in treating established cancers has not yet been fully realized; however, combination therapies targeting compensatory mechanisms have shown tolerability and efficacy in animal models and are currently being tested in clinical trials. As demonstrated in pre-clinical models, polyamine blocking therapy (PBT) reduces immunosuppression in the tumor microenvironment and enhances the therapeutic efficacy of immune checkpoint blockade (ICB). Thus, DFMO may sensitize tumors to other therapeutics, including immunotherapies and chemotherapies.

show abstract

“…Pro-inflammatory macrophage infiltration into adipose tissue is a hallmark of the metabolic inflammation of obesity that leads in fine to diabetes. Anderson-Baucum et al [ 130 ] found that the hypusinated form of eIF5A was increased in adipose tissue macrophages M1, which exhibit a proinflammatory phenotype in obese mice. They report that targeting DHPS in myeloid cells of obese mice decreased M1 macrophage infiltration and improved the sensitivity to insulin.…”

Section: Diabetes and Pancreasmentioning

confidence: 99%

The eukaryotic initiation factor 5A (eIF5A1), the molecule, mechanisms and recent insights into the pathophysiological roles

et al. 2021

View full text Add to dashboard Cite

Since the demonstration of its involvement in cell proliferation, the eukaryotic initiation factor 5A (eIF5A) has been studied principally in relation to the development and progression of cancers in which the isoform A2 is mainly expressed. However, an increasing number of studies report that the isoform A1, which is ubiquitously expressed in normal cells, exhibits novel molecular features that reveal its new relationships between cellular functions and organ homeostasis. At a first glance, eIF5A can be regarded, among other things, as a factor implicated in the initiation of translation. Nevertheless, at least three specificities: (1) its extreme conservation between species, including plants, throughout evolution, (2) its very special and unique post-translational modification through the activating-hypusination process, and finally (3) its close relationship with the polyamine pathway, suggest that the role of eIF5A in living beings remains to be uncovered. In fact, and beyond its involvement in facilitating the translation of proteins containing polyproline residues, eIF5A is implicated in various physiological processes including ischemic tolerance, metabolic adaptation, aging, development, and immune cell differentiation. These newly discovered physiological properties open up huge opportunities in the clinic for pathologies such as, for example, the ones in which the oxygen supply is disrupted. In this latter case, organ transplantation, myocardial infarction or stroke are concerned, and the current literature defines eIF5A as a new drug target with a high level of potential benefit for patients with these diseases or injuries. Moreover, the recent use of genomic and transcriptomic association along with metadata studies also revealed the implication of eIF5A in genetic diseases. Thus, this review provides an overview of eIF5A from its molecular mechanism of action to its physiological roles and the clinical possibilities that have been recently reported in the literature.

show abstract

Deoxyhypusine synthase promotes a pro-inflammatory macrophage phenotype

Cited by 39 publications

References 67 publications

A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease

A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease

Polyamine Depletion Strategies in Cancer: Remodeling the Tumor Immune Microenvironment to Enhance Anti-Tumor Responses

The eukaryotic initiation factor 5A (eIF5A1), the molecule, mechanisms and recent insights into the pathophysiological roles

Contact Info

Product

Resources

About