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Article: Butyrate and hexanoate-enriched triglycerides increase postprandrial systemic butyrate and hexanoate in men with overweight/obesity: A double-blind placebo-controlled randomized crossover trial.

van Deuren, Thirza / Smolders, Lotte / Hartog, Anita / Bouwman, Freek G / Holst, Jens J / Venema, Koen / Blaak, Ellen E / Canfora, Emanuel E

Frontiers in nutrition

2023 Volume 9, Page(s) 1066950

Abstract: Background: Short chain fatty acids (SCFA) are increasingly recognized for their potential ability to alleviate obesity-associated chronic low-grade inflammation and disturbed energy homeostasis. Evidence suggests that an increase in circulating SCFA ... ...

Abstract	Background: Short chain fatty acids (SCFA) are increasingly recognized for their potential ability to alleviate obesity-associated chronic low-grade inflammation and disturbed energy homeostasis. Evidence suggests that an increase in circulating SCFA might be necessary to induce beneficial alterations in energy metabolism. Objective: To compare the bioaccessibility of two different SCFA-enriched triglycerides: Akovita SCT (butyrate and hexanoate esterified with long chain fatty acids) and tributyrin/caproin (solely butyrate and hexanoate) and investigate whether the SCFA from orally administrated Akovita SCT reach the circulation and affect postprandial metabolism in men with overweight/obesity. Methods: The site, speed, and amount of SCFA release from Akovita SCT and tributyrin/caproin were assessed in a validated Results: In TIM-1, tributyrin/caproin was rapidly cleaved in the gastric compartment whereas the release of SCFA from Akovita SCT occurred predominantly in the small intestine. Conclusion: Esterifying SCFA-enriched triglycerides with long chain fatty acids delayed SCFA release from the glycerol backbone. Akovita SCT increased postprandial circulating butyrate and hexanoate without changing metabolic parameters in men with overweight/obesity. Future randomized clinical trials should investigate whether long-term Akovita SCT supplementation can aid in the treatment or prevention of metabolic disorders. Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT04662411.
Language	English
Publishing date	2023-01-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2776676-7
ISSN	2296-861X
ISSN	2296-861X
DOI	10.3389/fnut.2022.1066950
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Article ; Online: Protein arginine deiminase 4 inactivates tissue factor pathway inhibitor-alpha by enzymatic modification of functional arginine residues.

Thomassen, M Christella L G D / Bouwens, Bryan R C / Wichapong, Kanin / Suylen, Dennis P / Bouwman, Freek G / Hackeng, Tilman M / Koenen, Rory R

Journal of thrombosis and haemostasis : JTH

2023 Volume 21, Issue 5, Page(s) 1214–1226

Abstract: Background: Tissue factor pathway inhibitor (TFPI) is an important regulator of coagulation and a link between inflammation and thrombosis. During thrombotic events, TFPI is proteolytically inactivated by neutrophil elastase while bound to neutrophil ... ...

Abstract	Background: Tissue factor pathway inhibitor (TFPI) is an important regulator of coagulation and a link between inflammation and thrombosis. During thrombotic events, TFPI is proteolytically inactivated by neutrophil elastase while bound to neutrophil extracellular traps (NETs). Protein arginine deiminase 4 (PAD4) catalyzes the conversion of arginine to citrulline and is crucial for NET formation. Objectives: Here, we show that PAD4 inactivates full-length TFPIα by citrullination of its functional arginines. Methods: Citrullination of TFPIα and of TFPI-constructs by PAD4 was studied using western blotting and mass spectrometry. Binding of TFPIα to PAD4 was investigated using a solid-phase assay. Functional consequences were investigated by factor Xa inhibition and thrombin generation assays. Results: Nanomolar PAD4 amounts eliminated factor Xa inhibition by TFPIα. A citrullinated mutant Kunitz 2 domain did not inhibit factor Xa. Citrullination of TFPIα was found to be time- and concentration-dependent. Immunoprecipitation of citrullinated proteins from whole blood after neutrophil activation suggested the presence of TFPIα. Negatively charged phospholipids inhibited citrullination and truncated variants K1K2 and TFPI 1-161, and the isolated K2 domain were less efficiently citrullinated by PAD4. TFPIα bound to PAD4 with nanomolar affinity and involved the basic C-terminus. Thrombin generation in TFPI-deficient plasma demonstrated reduced anticoagulant activity of citrullinated TFPI. Mass spectrometry demonstrated citrullination of surface-exposed arginine residues in TFPIα after incubation with PAD4. Conclusion: Full-length TFPIα is sensitive to citrullination by PAD4, which causes loss of factor Xa inhibition. This process may play a role in the increased thrombosis risk associated with inflammation.
MeSH term(s)	Humans ; Protein-Arginine Deiminase Type 4 ; Factor Xa/metabolism ; Thrombin/metabolism ; Arginine ; Inflammation
Chemical Substances	lipoprotein-associated coagulation inhibitor ; Protein-Arginine Deiminase Type 4 (EC 3.5.3.15) ; Factor Xa (EC 3.4.21.6) ; Thrombin (EC 3.4.21.5) ; Arginine (94ZLA3W45F)
Language	English
Publishing date	2023-01-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1016/j.jtha.2023.01.017
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Zs.A 5805: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Fracture haematoma proteomics.

Groven, Rald V M / Kuik, Christel / Greven, Johannes / Mert, Ümit / Bouwman, Freek G / Poeze, Martijn / Blokhuis, Taco J / Huber-Lang, Markus / Hildebrand, Frank / Cillero-Pastor, Berta / van Griensven, Martijn

Bone & joint research

2024 Volume 13, Issue 5, Page(s) 214–225

Abstract: Aims: The aim of this study was to determine the fracture haematoma (fxH) proteome after multiple trauma using label-free proteomics, comparing two different fracture treatment strategies.: Methods: A porcine multiple trauma model was used in which ... ...

Abstract	Aims: The aim of this study was to determine the fracture haematoma (fxH) proteome after multiple trauma using label-free proteomics, comparing two different fracture treatment strategies. Methods: A porcine multiple trauma model was used in which two fracture treatment strategies were compared: early total care (ETC) and damage control orthopaedics (DCO). fxH was harvested and analyzed using liquid chromatography-tandem mass spectrometry. Per group, discriminating proteins were identified and protein interaction analyses were performed to further elucidate key biomolecular pathways in the early fracture healing phase. Results: The early fxH proteome was characterized by immunomodulatory and osteogenic proteins, and proteins involved in the coagulation cascade. Treatment-specific proteome alterations were observed. The fxH proteome of the ETC group showed increased expression of pro-inflammatory proteins related to, among others, activation of the complement system, neutrophil functioning, and macrophage activation, while showing decreased expression of proteins related to osteogenesis and tissue remodelling. Conversely, the fxH proteome of the DCO group contained various upregulated or exclusively detected proteins related to tissue regeneration and remodelling, and proteins related to anti-inflammatory and osteogenic processes. Conclusion: The early fxH proteome of the ETC group was characterized by the expression of immunomodulatory, mainly pro-inflammatory, proteins, whereas the early fxH proteome of the DCO group was more regenerative and osteogenic in nature. These findings match clinical observations, in which enhanced surgical trauma after multiple trauma causes dysbalanced inflammation, potentially leading to reduced tissue regeneration, and gained insights into regulatory mechanisms of fracture healing after severe trauma.
Language	English
Publishing date	2024-05-03
Publishing country	England
Document type	Journal Article
ZDB-ID	2669244-2
ISSN	2046-3758
ISSN	2046-3758
DOI	10.1302/2046-3758.135.BJR-2023-0323.R1
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Article ; Online: An in vitro model for hypertrophic adipocytes: Time-dependent adipocyte proteome and secretome changes under high glucose and high insulin conditions.

Qiao, Qi / Bouwman, Freek G / Renes, Johan / Mariman, Edwin C M

Journal of cellular and molecular medicine

2020 Volume 24, Issue 15, Page(s) 8662–8673

Abstract: Obesity is the consequence of a positive energy balance and characterized by enlargement of the adipose tissue, which in part is due to hyperplasia and hypertrophy of the adipocytes. Not much is known about the transition of normal mature adipocytes to ... ...

Abstract	Obesity is the consequence of a positive energy balance and characterized by enlargement of the adipose tissue, which in part is due to hyperplasia and hypertrophy of the adipocytes. Not much is known about the transition of normal mature adipocytes to the hypertrophic state, which in vivo is very hard to study. Here, we have maintained mature human SGBS cells as a surrogate for adipocytes, changes of morphological and molecular metabolism of the adipocytes were monitored over the first 4 days and the last 4 days. In total, 393 cellular proteins and 246 secreted proteins were identified for further analysis. During the first 4 days of high glucose and insulin, the adipocytes seemed to prefer pyruvate as energy source, whereas beta-oxidation was down-regulated supporting lipid loading. Over time, lipid droplet fusion instead of lipid uptake became relatively important for growth of lipid droplets during the last 4 days. Moreover, ECM production shifted towards ECM turnover by the up-regulation of proteases over eight days. The present in vitro system provides insight into the metabolic changes of adipocytes under conditions of high glucose and insulin, which may help to understand the process of in vivo adipocyte hypertrophy during the development of obesity.
MeSH term(s)	Adipocytes/cytology ; Adipocytes/metabolism ; Biomarkers ; Cell Size ; Cells, Cultured ; Chromatography, Liquid ; Glucose/metabolism ; Humans ; Insulins/metabolism ; Proteome/metabolism ; Proteomics/methods ; Signal Transduction ; Tandem Mass Spectrometry ; Time Factors
Chemical Substances	Biomarkers ; Insulins ; Proteome ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2020-07-03
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2074559-X
ISSN	1582-4934 ; 1582-4934 ; 1582-1838
ISSN (online)	1582-4934
ISSN	1582-4934 ; 1582-1838
DOI	10.1111/jcmm.15497
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Zs.A 5752: Show issues

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Article ; Online: Plasma Levels of Triglycerides and IL-6 Are Associated With Weight Regain and Fat Mass Expansion.

Qiao, Qi / Bouwman, Freek G / van Baak, Marleen A / Roumans, Nadia J T / Vink, Roel G / Mariman, Edwin C M

The Journal of clinical endocrinology and metabolism

2022 Volume 107, Issue 7, Page(s) 1920–1929

Abstract: Context: Long-term weight loss (WL) maintenance is the biggest challenge for overweight and obesity because of the almost unavoidable phenomenon of partial or even total weight regain (WR) after WL.: Objective: In the present study we investigated ... ...

Abstract	Context: Long-term weight loss (WL) maintenance is the biggest challenge for overweight and obesity because of the almost unavoidable phenomenon of partial or even total weight regain (WR) after WL. Objective: In the present study we investigated the relations of (the changes of) adipocyte size and other risk biomarkers with WR during the follow-up of the Yoyo dietary intervention. Methods: In this randomized controlled study, 48 overweight/obese participants underwent a very-low-calorie diet to lose weight, followed by a weight-stable period of 4 weeks and a follow-up period of 9 months. Anthropometric measurements, adipocyte volume of abdominal subcutaneous adipose tissue, and plasma metabolic parameters (free fatty acids [FFAs], triglycerides [TGs], total cholesterol, glucose, insulin, homeostasis model assessment of insulin resistance [HOMA-IR], interleukin 6 [IL-6], angiotensin-converting enzyme [ACE] activity, retinol binding protein 4 [RBP4]) at the beginning and the end of follow-up were analyzed. Results: Our results show that changes of TGs, IL-6, HOMA-IR, and ACE are significantly positively correlated with WR. Multiple linear regression analysis shows that only TG and IL-6 changes remained significantly correlated with WR and increased body fat mass. Moreover, the change in HOMA-IR was tightly correlated with the change in TGs. Surprisingly, change in adipocyte volume during follow-up was not correlated with WR nor with other factors, but positive correlations between adipocyte volume and HOMA-IR were found at the beginning and end of the follow-up. Conclusion: These results suggest that TGs and IL-6 are independently linked to WR via separate mechanisms, and that HOMA-IR and adipocyte volume may indirectly link to WR through the change of plasma TGs.
MeSH term(s)	Body Mass Index ; Humans ; Insulin Resistance ; Interleukin-6/metabolism ; Obesity/metabolism ; Overweight/metabolism ; Retinol-Binding Proteins, Plasma ; Triglycerides ; Weight Gain ; Weight Loss
Chemical Substances	Interleukin-6 ; RBP4 protein, human ; Retinol-Binding Proteins, Plasma ; Triglycerides
Language	English
Publishing date	2022-04-01
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	3029-6
ISSN	1945-7197 ; 0021-972X
ISSN (online)	1945-7197
ISSN	0021-972X
DOI	10.1210/clinem/dgac198
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Article: 2'-fucosyllactose alone or combined with resistant starch increases circulating short-chain fatty acids in lean men and men with prediabetes and obesity.

Canfora, Emanuel E / Vliex, Lars M M / Wang, Taojun / Nauta, Arjen / Bouwman, Freek G / Holst, Jens J / Venema, Koen / Zoetendal, Erwin G / Blaak, Ellen E

Frontiers in nutrition

2023 Volume 10, Page(s) 1200645

Abstract: Background: Infusion of short-chain fatty acids (SCFA) to the distal colon beneficially affects human substrate and energy metabolism. Here, we hypothesized that the combination of 2'-fucosyllactose (2'-FL) with resistant starch (RS) increases distal ... ...

Abstract	Background: Infusion of short-chain fatty acids (SCFA) to the distal colon beneficially affects human substrate and energy metabolism. Here, we hypothesized that the combination of 2'-fucosyllactose (2'-FL) with resistant starch (RS) increases distal colonic SCFA production and improves metabolic parameters. Methods: In this randomized, crossover study, 10 lean (BMI 20-24.9 kg/m Results: In lean men, supplementation with 2'-FL increased postprandial plasma acetate ( Conclusion: Supplementation of 2'-FL with/without RS the day before investigation increased systemic butyrate concentrations in lean men as well as in men with prediabetes and obesity, while acetate only increased in lean men. The combination of 2'-FL with RS showed a putatively beneficial metabolic effect by lowering plasma FFA in lean men, indicating a phenotype-specific effect. Clinical trial registration: nr. NCT04795804.
Language	English
Publishing date	2023-07-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2776676-7
ISSN	2296-861X
ISSN	2296-861X
DOI	10.3389/fnut.2023.1200645
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Article ; Online: GABARAPL1 is essential in extracellular vesicle cargo loading and metastasis development.

Beaumont, Joel E J / Ju, Jinzhe / Barbeau, Lydie M O / Demers, Imke / Savelkouls, Kim G / Derks, Kasper / Bouwman, Freek G / Wauben, Marca H M / Zonneveld, Marijke I / Keulers, Tom G H / Rouschop, Kasper M A

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology

2023 Volume 190, Page(s) 109968

Abstract: Background and purpose: Hypoxia is a common feature of tumours, associated with poor prognosis due to increased resistance to radio- and chemotherapy and enhanced metastasis development. Previously we demonstrated that GABARAPL1 is required for the ... ...

Abstract	Background and purpose: Hypoxia is a common feature of tumours, associated with poor prognosis due to increased resistance to radio- and chemotherapy and enhanced metastasis development. Previously we demonstrated that GABARAPL1 is required for the secretion of extracellular vesicles (EV) with pro-angiogenic properties during hypoxia. Here, we explored the role of GABARAPL1 Materials and methods: GABARAPL1 deficient or control MDA-MB-231 cells were injected in murine mammary fat pads. Lungs were dissected and analysed for human cytokeratin 18. EV from control and GABARAPL1 deficient cells exposed to normoxia (21% O Results: The number of pulmonary metastases derived from GABARAPL1 deficient tumours decreased by 84%. GABARAPL1 deficient cells migrate slower but display a comparable invasive capacity. Both normoxic and hypoxic EV contain proteins and miRNAs associated with metastasis development and, in line, increase cancer cell invasiveness. Although GABARAPL1 deficiency alters EV content, it does not alter the EV-induced increase in cancer cell invasiveness. Conclusion: GABARAPL1 is essential for metastasis development. This is unrelated to changes in migration and invasion and suggests that GABARAPL1 or GABARAPL1
MeSH term(s)	Humans ; Animals ; Mice ; MicroRNAs ; Hypoxia/metabolism ; Cell Hypoxia ; Neoplasms ; Extracellular Vesicles/metabolism ; Microtubule-Associated Proteins ; Adaptor Proteins, Signal Transducing/metabolism
Chemical Substances	MicroRNAs ; GABARAPL1 protein, human ; Microtubule-Associated Proteins ; Adaptor Proteins, Signal Transducing
Language	English
Publishing date	2023-10-28
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	605646-5
ISSN	1879-0887 ; 0167-8140
ISSN (online)	1879-0887
ISSN	0167-8140
DOI	10.1016/j.radonc.2023.109968
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Article ; Online: Heterogeneity of Lipid and Protein Cartilage Profiles Associated with Human Osteoarthritis with or without Type 2 Diabetes Mellitus.

Eveque-Mourroux, Maxime R / Emans, Pieter J / Boonen, Annelies / Claes, Britt S R / Bouwman, Freek G / Heeren, Ron M A / Cillero-Pastor, Berta

Journal of proteome research

2021 Volume 20, Issue 5, Page(s) 2973–2982

Abstract: Osteoarthritis (OA) is a multifactorial pathology and comprises a wide range of distinct phenotypes. In this context, the characterization of the different molecular profiles associated with each phenotype can improve the classification of OA. In ... ...

Abstract	Osteoarthritis (OA) is a multifactorial pathology and comprises a wide range of distinct phenotypes. In this context, the characterization of the different molecular profiles associated with each phenotype can improve the classification of OA. In particular, OA can coexist with type 2 diabetes mellitus (T2DM). This study investigates lipidomic and proteomic differences between human OA/T2DM
MeSH term(s)	Cartilage, Articular/diagnostic imaging ; Diabetes Mellitus, Type 2 ; Humans ; Lipids ; Osteoarthritis/diagnostic imaging ; Proteomics ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Chemical Substances	Lipids
Language	English
Publishing date	2021-04-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.1c00186
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Article: Heterogeneity of Lipid and Protein Cartilage Profiles Associated with Human Osteoarthritis with or without Type 2 Diabetes Mellitus

Eveque-Mourroux, Maxime R / Emans, Pieter J / Boonen, Annelies / Claes, Britt S. R / Bouwman, Freek G / Heeren, Ron M. A / Cillero-Pastor, Berta

Journal of proteome research. 2021 Apr. 17, v. 20, no. 5

2021

Abstract	Osteoarthritis (OA) is a multifactorial pathology and comprises a wide range of distinct phenotypes. In this context, the characterization of the different molecular profiles associated with each phenotype can improve the classification of OA. In particular, OA can coexist with type 2 diabetes mellitus (T2DM). This study investigates lipidomic and proteomic differences between human OA/T2DM– and OA/T2DM⁺ cartilage through a multimodal mass spectrometry approach. Human cartilage samples were obtained after total knee replacement from OA/T2DM– and OA/T2DM⁺ patients. Label-free proteomics was employed to study differences in protein abundance and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) for spatially resolved-lipid analysis. Label-free proteomic analysis showed differences between OA/T2DM– and OA/T2DM⁺ phenotypes in several metabolic pathways such as lipid regulation. Interestingly, phospholipase A2 protein was found increased within the OA/T2DM⁺ cohort. In addition, MALDI-MSI experiments revealed that phosphatidylcholine and sphingomyelin species were characteristic of the OA/T2DM– group, whereas lysolipids were more characteristic of the OA/T2DM⁺ phenotype. The data also pointed out differences in phospholipid content between superficial and deep layers of the cartilage. Our study shows distinctively different lipid and protein profiles between OA/T2DM– and OA/T2DM⁺ human cartilage, demonstrating the importance of subclassification of the OA disease for better personalized treatments.
Keywords	cartilage ; desorption ; humans ; ionization ; lipidomics ; mass spectrometry ; noninsulin-dependent diabetes mellitus ; osteoarthritis ; phenotype ; phosphatidylcholines ; phospholipase A2 ; prostheses ; proteome ; proteomics ; research ; sphingomyelins
Language	English
Dates of publication	2021-0417
Size	p. 2973-2982.
Publishing place	American Chemical Society
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	2078618-9
ISSN	1535-3907 ; 1535-3893
ISSN (online)	1535-3907
ISSN	1535-3893
DOI	10.1021/acs.jproteome.1c00186
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Glucose Restriction Plus Refeeding in Vitro Induce Changes of the Human Adipocyte Secretome with an Impact on Complement Factors and Cathepsins.

Qiao, Qi / Bouwman, Freek G / Baak, Marleen A van / Renes, Johan / Mariman, Edwin C M

International journal of molecular sciences

2019 Volume 20, Issue 16

Abstract: Adipose tissue is a major endocrine organ capable of secreting adipokines with a role in whole-body metabolism. Changes in the secretome profile during the development of obesity is suspected to contribute to the risk of health complications such as ... ...

Abstract	Adipose tissue is a major endocrine organ capable of secreting adipokines with a role in whole-body metabolism. Changes in the secretome profile during the development of obesity is suspected to contribute to the risk of health complications such as those associated with weight regain after weight loss. However, the number of studies on weight regain is limited and secretome changes during weight regain have hardly been investigated. In an attempt to generate leads for in vivo studies, we have subjected human Simpson Golabi Behmel Syndrome adipocytes to glucose restriction (GR) followed by refeeding (RF) as an in vitro surrogate for weight regain after weight loss. Using LC-MS/MS, we compared the secreted protein profile after GR plus RF with that of normal feeding (NF) to assess the consequences of GR plus RF. We identified 338 secreted proteins of which 49 were described for the first time as being secreted by adipocytes. In addition, comparison between NF and GR plus RF showed 39 differentially secreted proteins. Functional classification revealed GR plus RF-induced changes of enzymes for extracellular matrix modification, complement system factors, cathepsins, and several proteins related to Alzheimer's disease. These observations can be used as clues to investigate metabolic consequences of weight regain, weight cycling or intermittent fasting.
MeSH term(s)	Adipocytes/cytology ; Adipocytes/drug effects ; Adipokines/metabolism ; Cathepsins/metabolism ; Cells, Cultured ; Chromatography, Liquid ; Extracellular Matrix/drug effects ; Extracellular Matrix/metabolism ; Glucose/pharmacology ; Humans ; Tandem Mass Spectrometry
Chemical Substances	Adipokines ; Cathepsins (EC 3.4.-) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2019-08-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms20164055
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