Variation in the Phosphoinositide 3-Kinase Gamma Gene Affects Plasma HDL-Cholesterol without Modification of Metabolic or Inflammatory Markers

Kächele, Martin; Hennige, Anita M.; Machann, Jürgen; Hieronimus, Anja; Lamprinou, Apostolia; Machicao, Fausto; Schick, Fritz; Fritsche, Andreas; Stefan, Norbert; Nürnberg, Bernd; Häring, Hans‐Ulrich; Staiger, Harald

doi:10.1371/journal.pone.0144494

Cited by 19 publications

(14 citation statements)

References 39 publications

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“…A recent study showed association of genetic mutations in PI3Kγ gene affecting plasma cholesterol. However, the single nucleotide polymorphisms (SNPs) reported in this study are present in the intronic region or the SNP leads to synonymous mutations[68] with altering the primary amino-acid sequence. These observations suggest that more studies are needed to assess for SNPs in the genome related to the sequences associated with coding regions of the protein.…”

Section: Pi3kγ As a Scaffold In Other Systemsmentioning

confidence: 99%

Scaffolding Function of PI3Kgamma Emerges from Enzyme's Shadow

Mohan

Prasad

2017

Journal of Molecular Biology

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Traditionally an enzyme is a protein that mediates biochemical action by binding to the substrate and catalyzing the reaction that translates external cues into biological responses. Sequential dissemination of information from one enzyme to another facilitates signal transduction in biological systems providing for feed-forward and feedback mechanisms. Given this view-point, an enzyme without its catalytic activity is generally considered to be an inert organizational protein without catalytic function and has classically been termed as pseudoenzymes. However, pseudoenzymes still have biological function albeit non-enzymatic like serving as a chaperone protein or an interactive platform between proteins. In this regard, majority of the studies have focused solely on the catalytic role of enzymes in biological function overlooking the potentially critical non-enzymatic roles. Increasing evidence from recent studies implicate that scaffolding function of enzymes could be as important in signal transduction as its catalytic activity an antithesis to the definition of enzymes. Recognition of non-enzymatic functions could be critical as these unappreciated roles may hold clues to the ineffectiveness of kinase-inhibitors in pathology, which is characteristically associated with increased enzyme expression. Using an established enzyme phosphoinositide 3-kinase γ (PI3Kγ), we discuss the insights obtained from the scaffolding function and how this non-canonical role could contribute to/alter the outcomes in pathology like cancer and heart failure. Also we hope that with this review, we provide a forum and a starting point to discuss the idea that catalytic function alone may not account for all the actions observed with increased expression of the enzyme.

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Section: Pi3kγ As a Scaffold In Other Systemsmentioning

confidence: 99%

Scaffolding Function of PI3Kgamma Emerges from Enzyme's Shadow

Mohan

Prasad

2017

Journal of Molecular Biology

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“…In monogastrics, liver is the primary site for fatty acids oxidation and ketone bodies production[29, 30]. The liver-synthesized cholesterol accounts for more than 80% of the total cholesterol produced by the body, and is the main source of plasma cholesterol [31].…”

Section: Introductionmentioning

confidence: 99%

Transcriptome analysis of fasting caecotrophy on hepatic lipid metabolism in New Zealand rabbits

Wang

Sun

et al. 2018

Preprint

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Background: Rabbit produce two kinds of feces: hard and soft feces, and they have a preference for consuming the latter. Although this habit of rabbits has been reported for many years, little is known on whether this behavior will impact growth performance and metabolism. The RNA-Seq technology is an effective means of analyzing transcript groups to clarify molecular mechanisms. The aim of the present study was to investigate the effects of fasting caecotrophy on growth performance and lipid metabolism in rabbits. Results:Our results indicated that, compared with the control group, the final body weight, weight gain, liver weight, specific growth rate and feed conversion ratio were all decreased in the experimental group (P<0.05). Oil red staining of the liver tissue indicated that fasting caecotrophy resulted in decrease of lipid droplet accumulation. RNA sequencing (RNA-seq) analysis revealed a total of 301.2 million raw reads approximately 45.06 Gb of high-quality clean data. The data were mapped to the rabbit genome (http://www.ensembl.org/Oryctolagus_cuniculus). After a five step filtering process, 14964 genes were identified, including 444 differentially expressed genes (P<0.05, foldchange≥1). Especially for remarkable changes of genes related to lipid metabolism, RT-PCR further validated the remarkable decrease of these genes in fasting caecotrophy group, including CYP7A1, PPARG, ABCA1, ABCB1, ABCG1, GPAM, SREBP, etc. KEGG annotation of the differentially expressed genes indicated that the main pathways affected were retinol metabolism, pentose and glucuronide interactions, starch and sucrose metabolism, fatty acid degradation, steroid hormone biosynthesis. Conclusion:In conclusion, the present study revealed that banning caecotrophy reduced growth rate and altered lipid metabolism, our results laid instructive basis for rabbit feeding and production. These data also provides a reference for studying the effects of soft feces on other small herbivores. Introduction 2 Many small herbivores have a natural instinct of caecotrophy[1]. Because of the 3 small body shape and their digestive tract volume is limited, the average residence 4 time of food in the digestive tract is relatively short [2, 3]. In order to meet their 5 nutrition needs, small herbivores need to obtain adequate high-quality food[4]. Small 6 herbivores mainly rely on low-quality, high-fiber plant stems and leaves as food 7 sources, with cellulose from symbiotic microorganisms in the hind-gut aiding in 8 digestion[5, 6]. Because microbial fermentation takes longer time than the average 9 residence time of food in the digestive tract, increasing digestibility by ingesting 10 incompletely-digested nutrients is an important nutritional strategy for small 11 herbivores [7-9]. 12 There are two types of feces excreted by rabbits: hard feces (nutrient-poor) and 13 soft feces (consist of protein, vitamins, and inorganic salts) [10-12]. Soft feces also 14 contain a large number of microorganisms, which are important for microbial 15 fermentation in he...

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“…rs17398575, rs17477177, and rs342286 are located near PIK3CG and were associated with cardiovascular diseases risk ( 74 – 76 ). The PIK3CG SNP rs342286 was associated with epinephrine-induced aggregation ( 77 ) and the SNPs rs4288294 and rs116697954 associate with higher HDL2 cholesterol plasma levels and rs1129293, also evaluated in our study, was associated with lower HDL levels ( 78 ). Genetic association studies have been extensively used to search host factors that predispose to severe outcomes during influenza infection [reviewed in Ref.…”

Section: Discussionmentioning

confidence: 55%

Phosphatidyl Inositol 3 Kinase-Gamma Balances Antiviral and Inflammatory Responses During Influenza A H1N1 Infection: From Murine Model to Genetic Association in Patients

et al. 2018

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Influenza A virus (IAV) infection causes severe pulmonary disease characterized by intense leukocyte infiltration. Phosphoinositide-3 kinases (PI3Ks) are central signaling enzymes, involved in cell growth, survival, and migration. Class IB PI3K or phosphatidyl inositol 3 kinase-gamma (PI3Kγ), mainly expressed by leukocytes, is involved in cell migration during inflammation. Here, we investigated the contribution of PI3Kγ for the inflammatory and antiviral responses to IAV. PI3Kγ knockout (KO) mice were highly susceptible to lethality following infection with influenza A/WSN/33 H1N1. In the early time points of infection, infiltration of neutrophils was higher than WT mice whereas type-I and type-III IFN expression and p38 activation were reduced in PI3Kγ KO mice resulting in higher viral loads when compared with WT mice. Blockade of p38 in WT macrophages infected with IAV reduced levels of interferon-stimulated gene 15 protein to those induced in PI3Kγ KO macrophages, suggesting that p38 is downstream of antiviral responses mediated by PI3Kγ. PI3Kγ KO-derived fibroblasts or macrophages showed reduced type-I IFN transcription and altered pro-inflammatory cytokines suggesting a cell autonomous imbalance between inflammatory and antiviral responses. Seven days after IAV infection, there were reduced infiltration of natural killer cells and CD8+ T lymphocytes, increased concentration of inflammatory cytokines in bronchoalveolar fluid, reduced numbers of resolving macrophages, and IL-10 levels in PI3Kγ KO. This imbalanced environment in PI3Kγ KO-infected mice culminated in enhanced lung neutrophil infiltration, reactive oxygen species release, and lung damage that together with the increased viral loads, contributed to higher mortality in PI3Kγ KO mice compared with WT mice. In humans, we tested the genetic association of disease severity in influenza A/H1N1pdm09-infected patients with three potentially functional PIK3CG single-nucleotide polymorphisms (SNPs), rs1129293, rs17847825, and rs2230460. We observed that SNPs rs17847825 and rs2230460 (A and T alleles, respectively) were significantly associated with protection from severe disease using the recessive model in patients infected with influenza A(H1N1)pdm09. Altogether, our results suggest that PI3Kγ is crucial in balancing antiviral and inflammatory responses to IAV infection.

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Variation in the Phosphoinositide 3-Kinase Gamma Gene Affects Plasma HDL-Cholesterol without Modification of Metabolic or Inflammatory Markers

Cited by 19 publications

References 39 publications

Scaffolding Function of PI3Kgamma Emerges from Enzyme's Shadow

Scaffolding Function of PI3Kgamma Emerges from Enzyme's Shadow

Transcriptome analysis of fasting caecotrophy on hepatic lipid metabolism in New Zealand rabbits

Phosphatidyl Inositol 3 Kinase-Gamma Balances Antiviral and Inflammatory Responses During Influenza A H1N1 Infection: From Murine Model to Genetic Association in Patients

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