AIBP: A Novel Molecule at the Interface of Cholesterol Transport, Angiogenesis, and Atherosclerosis

Zhu, Laurence; Fang, Longhou

doi:10.14797/mdcj-11-3-160

Cited by 12 publications

(9 citation statements)

References 75 publications

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“…The NAD(P)HX dehydratase and epimerase are two members of a growing list of enzymes that have been recognized in recent years to participate in a process called metabolite repair or metabolite proofreading and in which a panoply of protective enzymatic activities are required to prevent the accumulation of non-canonical, potentially toxic metabolites that are formed continuously via enzymatic side reactions or spontaneous chemical reactions [11][12][13][14]. The NAXE protein has been reported by other investigators to play a role in cholesterol efflux and angiogenesis [15][16][17]; it remains unclear how this role could be reconciled with the metabolite repair function [18].…”

Section: Introductionmentioning

confidence: 99%

NAD(P)HX repair deficiency causes central metabolic perturbations in yeast and human cells

Becker-Kettern

Paczia

Conrotte

et al. 2018

Preprint

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reading frame; PSAT1, phosphoserine transaminase 1. Keywords-metabolite repair, NAD(P)HX dehydratase, NAD(P)HX epimerase, Saccharomyces cerevisiae, inborn errors of metabolism.Conflict of interest-The authors declare that they have no conflicts of interest with the contents of this article.. CC-BY-NC-ND 4.0 International license It is made available under a (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/302257 doi: bioRxiv preprint first posted online Apr. 16, 2018; 2 ABSTRACT NADHX and NADPHX are hydrated and redox inactive forms of the NADH and NADPH cofactors, known to inhibit several dehydrogenases in vitro. A metabolite repair system that is conserved in all domains of life and that comprises the two enzymes NAD(P)HX dehydratase and NAD(P)HX epimerase, allows reconversion of both the S-and R-epimers of NADHX and NADPHX to the normal cofactors. An inherited deficiency in this system has recently been shown to cause severe neurometabolic disease in children. Although evidence for the presence of NAD(P)HX has been obtained in plant and human cells, little is known about the mechanism of formation of these derivatives in vivo and their potential effects on cell metabolism. Here, we show that NAD(P)HX dehydratase deficiency in yeast leads to an important, temperature-dependent NADHX accumulation in quiescent cells with a concomitant depletion of intracellular NAD + and serine pools. We demonstrate that NADHX potently inhibits the first step of the serine synthesis pathway in yeast. Human cells deficient in the NAD(P)HX dehydratase also accumulated NADHX and showed decreased viability. In addition, those cells consumed more glucose and produced more lactate, potentially indicating impaired mitochondrial function. Our results provide first insights into how NADHX accumulation affects cellular functions and pave the way for a better understanding of the mechanism(s) underlying the rapid and severe neurodegeneration leading to early death in NADHX repair deficient children.

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Section: Introductionmentioning

confidence: 99%

NAD(P)HX repair deficiency causes central metabolic perturbations in yeast and human cells

Becker-Kettern

Paczia

Conrotte

et al. 2018

Preprint

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“…ApoAI binding protein (AIBP) is secreted from tissue and physically binds with apoAI (13). AIBP accelerates cholesterol efflux from endothelial cells to HDL-C thereby regulating angiogenesis via alterations in the composition of the lipid rafts, possibly due to reduced caveolin-1 (CAV-1) and as well as interfering with VEGFR2 signalling (14,15). Alteration in angiogenic factors have been repeatedly observed in pre-eclamptic placentae (16) with decreased VEGF-A and VEGFR1 in the cytotrophoblast.…”

Section: Introductionmentioning

confidence: 99%

“…They observed that both AIBP and HDL-C mediated cholesterol efflux alters the composition of the lipid rafts, due to reduced CAV-1, as well as interfering with vascular endothelial growth factor receptor 1 (VEGFR2; KDR) dimerization and signalling, thus inhibiting VEGF-induced angiogenesis (14,15). The authors concluded that AIBP positively regulates cholesterol efflux from endothelial cells and that effective cholesterol efflux is critical for proper angiogenesis (14).…”

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confidence: 99%

Increased maternal and fetal cholesterol efflux capacity and placental CYP27A1 expression in preeclampsia

Mistry

Kurlak

Mansour

et al. 2017

Journal of Lipid Research

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“…In addition to the high-throughput screening identification of transthyretin (TTR) as a potential C . burnetii target involved in cholesterol processing [ 101 ], complementary testing confirmed two additional host proteins involved in cholesterol handling: the apolipoprotein APOA1BP [ 102 ] and the intracellular cholesterol transporter NPC2 [ 103 ]. Although C .…”

Section: Resultsmentioning

confidence: 99%

Mechanisms of action of Coxiella burnetii effectors inferred from host-pathogen protein interactions

et al. 2017

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Coxiella burnetii is an obligate Gram-negative intracellular pathogen and the etiological agent of Q fever. Successful infection requires a functional Type IV secretion system, which translocates more than 100 effector proteins into the host cytosol to establish the infection, restructure the intracellular host environment, and create a parasitophorous vacuole where the replicating bacteria reside. We used yeast two-hybrid (Y2H) screening of 33 selected C. burnetii effectors against whole genome human and murine proteome libraries to generate a map of potential host-pathogen protein-protein interactions (PPIs). We detected 273 unique interactions between 20 pathogen and 247 human proteins, and 157 between 17 pathogen and 137 murine proteins. We used orthology to combine the data and create a single host-pathogen interaction network containing 415 unique interactions between 25 C. burnetii and 363 human proteins. We further performed complementary pairwise Y2H testing of 43 out of 91 C. burnetii-human interactions involving five pathogen proteins. We used the combined data to 1) perform enrichment analyses of target host cellular processes and pathways, 2) examine effectors with known infection phenotypes, and 3) infer potential mechanisms of action for four effectors with uncharacterized functions. The host-pathogen interaction profiles supported known Coxiella phenotypes, such as adapting cell morphology through cytoskeletal re-arrangements, protein processing and trafficking, organelle generation, cholesterol processing, innate immune modulation, and interactions with the ubiquitin and proteasome pathways. The generated dataset of PPIs—the largest collection of unbiased Coxiella host-pathogen interactions to date—represents a rich source of information with respect to secreted pathogen effector proteins and their interactions with human host proteins.

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AIBP: A Novel Molecule at the Interface of Cholesterol Transport, Angiogenesis, and Atherosclerosis

Cited by 12 publications

References 75 publications

NAD(P)HX repair deficiency causes central metabolic perturbations in yeast and human cells

NAD(P)HX repair deficiency causes central metabolic perturbations in yeast and human cells

Increased maternal and fetal cholesterol efflux capacity and placental CYP27A1 expression in preeclampsia

Mechanisms of action of Coxiella burnetii effectors inferred from host-pathogen protein interactions

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