Circulating Inhibitory Factor 1 levels in adult patients with Prader–Willi syndrome

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Maurizio Delvecchio ◽  
Graziano Grugni ◽  
Stefania Mai ◽  
Elvira Favoino ◽  
Annalisa Ingletto ◽  
...  
Keyword(s):  
Regulatory Protein ◽  
Hdl Cholesterol ◽  
Premature Death ◽  
Adult Patients ◽  
Inhibitory Factor ◽  
Prader Willi Syndrome ◽  
Clinical Genetic ◽  
Genetic Syndrome ◽  
Mitochondrial Atp Synthase ◽  
Inhibitory Factor 1

Abstract Objectives Prader–Willi syndrome (PWS) is a rare genetic syndrome characterized by hyperphagia and early development of morbid obesity. Cardiovascular disease (CVD) and metabolic syndrome (MetS) are major comorbidities in these patients leading to premature death. Inhibitory factor 1 (IF1) works as a regulatory protein, inhibiting the ATP hydrolase activity of mitochondrial ATP synthase and likely playing a role in lipid metabolism. We aimed to assay IF1 in adult patients with PWS evaluating any relationship with clinical, genetic and biochemical parameters. Methods We recruited 35 adult patients with genetically confirmed PWS. Results IF1 serum concentration displayed a normal distribution with an average value of 70.7 ± 22.6 pg/mL, a median value of 66.1 pg/mL. It was above the reference range only in one patient. All parameters were compared from both sides of IF1 median without displaying any significant differences. Patients with normal or low HDL-cholesterol did not present any difference as regards IF1 levels, which were not different between patients with and without MetS. Non-esterified fatty acids (NEFA) serum levels (r=0.623; p<0.001) showed a statistically significant correlation with IF1. Cholesterol and its fractions did not present any correlation with IF1. Conclusions In this study we do not confirm that HDL-cholesterol and IF1 are correlated, but we show that in adult PWS patients, NEFA are correlated with serum IF1. This protein could play a role to some extent in determining the complex metabolic alterations in PWS patients.

scholarly journals Dietary cholesterol supplementation and inhibitory factor 1 serum levels in two dizygotic Smith-Lemli-Opitz syndrome twins: a case report

2020 ◽  
Vol 46 (1) ◽  
Author(s):  
Maurizio Delvecchio ◽  
Biagio Rapone ◽  
Simonetta Simonetti ◽  
Simona Fecarotta ◽  
Graziana De Carlo ◽  
...  
Keyword(s):  
Cholesterol Biosynthesis ◽  
Neurodevelopmental Disorder ◽  
Mitochondrial Protein ◽  
Dietary Cholesterol ◽  
Hdl Cholesterol ◽  
Inhibitory Factor ◽  
Cholesterol Intake ◽  
Opitz Syndrome ◽  
Cholesterol Supplementation ◽  
Inhibitory Factor 1

Abstract Background Smith-Lemli-Opitz syndrome (SLOS) is a rare genetic neurodevelopmental disorder caused by the defect in the 7-dehydrocholesterol reductase. This defect leads to the deficiency of cholesterol biosynthesis with accumulation of 7-dehydrocholesterol. Inhibitory factor 1 (IF1) is a well-known mitochondrial protein. Recently, it has been discovered in the human serum where it is reported to be involved in the HDL-cholesterol intake. Here we report the IF1 presence in the serum of two paediatric SLOS dizygotic twins treated with dietary cholesterol supplementation. Case presentation The patients showed a typical phenotype. They started dietary supplementation with cholesterol when 2 months old. The cholesterol intake was periodically titrated on the basis of weight increase and the twin 1 required a larger supplementation than the twin 2 during the follow-up. When 6.4-year-old, they underwent IF1 assay that was 7-fold increased in twin 2 compared to twin 1 (93.0 pg/ml vs 13.0 pg/ml, respectively). Conclusions We report, for the first time, the presence of circulating IF1 in the serum of SLOS patients, showing different levels among them. Our findings confirm that IF1 could be a novel research target in cholesterol-related disorders and also in SLOS, and could contribute to the general debate on IF1 as a new modulator of cholesterol levels.

scholarly journals Generation of mitochondrial reactive oxygen species is controlled by ATPase inhibitory factor 1 and regulates cognition

PLoS Biology ◽  
2021 ◽  
Vol 19 (5) ◽  
pp. e3001252
Author(s):  
Pau B. Esparza-Moltó ◽  
Inés Romero-Carramiñana ◽  
Cristina Núñez de Arenas ◽  
Marta P. Pereira ◽  
Noelia Blanco ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Synaptic Transmission ◽  
Atp Synthase ◽  
Reactive Oxygen ◽  
Synaptic Function ◽  
Inhibitory Factor ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species ◽  
Mitochondrial Atp Synthase ◽  
Inhibitory Factor 1

The mitochondrial ATP synthase emerges as key hub of cellular functions controlling the production of ATP, cellular signaling, and fate. It is regulated by the ATPase inhibitory factor 1 (IF1), which is highly abundant in neurons. Herein, we ablated or overexpressed IF1 in mouse neurons to show that IF1 dose defines the fraction of active/inactive enzyme in vivo, thereby controlling mitochondrial function and the production of mitochondrial reactive oxygen species (mtROS). Transcriptomic, proteomic, and metabolomic analyses indicate that IF1 dose regulates mitochondrial metabolism, synaptic function, and cognition. Ablation of IF1 impairs memory, whereas synaptic transmission and learning are enhanced by IF1 overexpression. Mechanistically, quenching the IF1-mediated increase in mtROS production in mice overexpressing IF1 reduces the increased synaptic transmission and obliterates the learning advantage afforded by the higher IF1 content. Overall, IF1 plays a key role in neuronal function by regulating the fraction of ATP synthase responsible for mitohormetic mtROS signaling.

scholarly journals Mitochondrial Inhibitory Factor 1 (IF1) Is Present in Human Serum and Is Positively Correlated with HDL-Cholesterol

PLoS ONE ◽  
2011 ◽  
Vol 6 (9) ◽  
pp. e23949 ◽  
Author(s):  
Annelise Genoux ◽  
Véronique Pons ◽  
Claudia Radojkovic ◽  
Florence Roux-Dalvai ◽  
Guillaume Combes ◽  
...  
Keyword(s):  
Human Serum ◽  
Hdl Cholesterol ◽  
Inhibitory Factor ◽  
Inhibitory Factor 1

scholarly journals A reference measurement of circulating ATPase inhibitory factor 1 (IF1) in humans by LC-MS/MS: comparison with conventional ELISA

2020 ◽  
Author(s):  
Annelise Genoux ◽  
Thibaut Duparc ◽  
Jean-Bernard Ruidavets ◽  
Cecile Ingueneau ◽  
Souad Najib ◽  
...  
Keyword(s):  
Human Plasma ◽  
Plasma Levels ◽  
Atp Hydrolysis ◽  
Hdl Cholesterol ◽  
Systemic Circulation ◽  
Inhibitory Factor ◽  
Enzyme Linked Immunosorbent Assay ◽  
Strongly Correlated ◽  
Liquid Chromatography Tandem Mass ◽  
Inhibitory Factor 1

ATPase inhibitory factor 1 (IF1) is a 9.5 kDa protein that binds to mitochondrial and plasma membrane ATP synthase and selectively inhibits ATP hydrolysis. Recently, IF1 was identified in systemic circulation in humans. IF1 appeared as an independent determinant of HDL-cholesterol with lower levels in coronary heart disease (CHD) patients. Moreover, IF1 was also found to negatively associate with mortality in these patients, supporting the notion that circulating IF1 could be a promising biomarker of cardiovascular disease. However, in previous studies, IF1 was quantified by a non-standardized competitive enzyme-linked immunosorbent assay (ELISA). Herein, we have validated a liquid chromatography-tandem mass spectrometry method (LC-MS/MS) enabling the accurate quantification of IF1 in human plasma. Plasma IF1 was trypsin-digested through an optimized procedure before LC-MS/MS analysis. The method was successfully validated over 4 independent experiments into the range of 100-1,500 ng/mL. Intra- and inter-assay variation coefficients had never exceeded 14.2% and accuracy ranged between 95% and 102% for the selected EAGGAFGK peptide marker. Subsequently, the results of the LC-MS/MS method were compared with those obtained using ELISA in 204 individuals from the GENES study. We found that IF1 plasma levels obtained using both techniques were strongly correlated (r =0.89, p <0.0001), while the Bland-Altman plot did not indicate any major statistically significant differences. To clinically validate LC-MS/MS, we confirmed the positive correlation between IF1 plasma levels and HDL-cholesterol (r =0.38, p <0.0001). Besides, we found lower IF1 plasma levels in CHD patients compared to controls (431 +/- 132 ng/mL and 555 +/- 173 ng/mL, respectively; p <0.0001). Hence, it can be concluded that the presented LC-MS/MS method provides a highly specific strategy for IF1 quantification in human plasma and could be proposed as a reference technique.

scholarly journals Promoter methylation of WNT inhibitory factor-1 may be associated with the pathogenesis of multiple human tumors

2018 ◽  
Vol 14 (9) ◽  
pp. 381 ◽  
Author(s):  
Jianliang Zhang ◽  
Yong Zhou ◽  
Zhaohua Li ◽  
Yinlu Ding ◽  
Peng Zhang ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Human Tumors ◽  
Inhibitory Factor ◽  
Wnt Inhibitory Factor 1 ◽  
Inhibitory Factor 1

scholarly journals Evaluating macrophage migration inhibitory factor 1 expression as a prognostic biomarker in colon cancer

Tumor Biology ◽  
2020 ◽  
Vol 42 (6) ◽  
pp. 101042832092452
Author(s):  
Lina Olsson ◽  
Gudrun Lindmark ◽  
Marie-Louise Hammarström ◽  
Sten Hammarström ◽  
Basel Sitohy
Keyword(s):  
Colon Cancer ◽  
Lymph Nodes ◽  
Mrna Expression ◽  
Cancer Patients ◽  
Migration Inhibitory Factor ◽  
Inhibitory Factor ◽  
Expression Levels ◽  
Significant Difference ◽  
Mrna Expression Levels ◽  
Inhibitory Factor 1

Objective: Several studies indicate that macrophage migration inhibitory factor 1 plays a role for tumor progression in colon cancer. We investigated whether determination of migration inhibitory factor 1 mRNA expression levels in lymph nodes of colon cancer patients could be used as a prognostic marker. Methods: Expression levels of migration inhibitory factor 1 and carcinoembryonic antigen mRNAs were assessed in primary tumors and regional lymph nodes of 123 colon cancer patients (stages I–IV), and in colon cancer- and immune cell lines using quantitative reverse transcriptase–polymerase chain reaction. Expression of migration inhibitory factor 1 protein was investigated by two-color immunohistochemistry and immunomorphometry. Results: Migration inhibitory factor 1 mRNA was expressed at 60 times higher levels in primary colon cancer tumors compared to normal colonic tissue (medians 8.2 and 0.2 mRNA copies/18S rRNA unit; p < .0001). A highly significant difference in mRNA expression levels was found between hematoxylin-eosin positive lymph nodes and hematoxylin-eosin negative lymph nodes (p < .0001). Migration inhibitory factor 1 and carcinoembryonic antigen proteins were simultaneously expressed in many colon cancer-tumor cells. Kaplan–Meier survival model and hazard ratio analysis, using a cutoff level at 2.19 mRNA copies/18S rRNA unit, revealed that patients with lymph nodes expressing high levels of migration inhibitory factor 1 mRNA had a 3.5-fold (p = .04) higher risk for recurrence, associated with a small, but significant, difference in mean survival time (7 months, p = .03) at 12 years of follow-up. Conclusion: Although migration inhibitory factor 1 mRNA expression levels were related to severity of disease and lymph node analysis revealed that colon cancer patients with high levels had a shorter survival time after surgery than those with low levels, the difference was small and probably not useful in clinical practice.

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