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van den Brand AD, Bajard L, Steffensen IL, Brantsæter AL, Dirven HAAM, Louisse J, Peijnenburg A, Ndaw S, Mantovani A, De Santis B, Mengelers MJB. Providing Biological Plausibility for Exposure-Health Relationships for the Mycotoxins Deoxynivalenol (DON) and Fumonisin B1 (FB1) in Humans Using the AOP Framework. Toxins (Basel) 2022; 14:279. [PMID: 35448888 PMCID: PMC9030459 DOI: 10.3390/toxins14040279] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/04/2022] [Accepted: 04/10/2022] [Indexed: 02/07/2023] Open
Abstract
Humans are chronically exposed to the mycotoxins deoxynivalenol (DON) and fumonisin B1 (FB1), as indicated by their widespread presence in foods and occasional exposure in the workplace. This exposure is confirmed by human biomonitoring (HBM) studies on (metabolites of) these mycotoxins in human matrices. We evaluated the exposure-health relationship of the mycotoxins in humans by reviewing the available literature. Since human studies did not allow the identification of unequivocal chronic health effects upon exposure to DON and FB1, the adverse outcome pathway (AOP) framework was used to structure additional mechanistic evidence from in vitro and animal studies on the identified adverse effects. In addition to a preliminary AOP for DON resulting in the adverse outcome (AO) 'reduced body weight gain', we developed a more elaborated AOP for FB1, from the molecular initiating event (MIE) 'inhibition of ceramide synthases' leading to the AO 'neural tube defects'. The mechanistic evidence from AOPs can be used to support the limited evidence from human studies, to focus FB1- and DON-related research in humans to identify related early biomarkers of effect. In order to establish additional human exposure-health relationships in the future, recommendations are given to maximize the information that can be obtained from HBM.
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Affiliation(s)
| | - Lola Bajard
- RECETOX, Faculty of Science, Masaryk University, Kotlarska 2, 611 37 Brno, Czech Republic;
| | - Inger-Lise Steffensen
- Norwegian Institute of Public Health (NIPH), 0213 Oslo, Norway; (I.-L.S.); (A.L.B.); (H.A.A.M.D.)
| | - Anne Lise Brantsæter
- Norwegian Institute of Public Health (NIPH), 0213 Oslo, Norway; (I.-L.S.); (A.L.B.); (H.A.A.M.D.)
| | - Hubert A. A. M. Dirven
- Norwegian Institute of Public Health (NIPH), 0213 Oslo, Norway; (I.-L.S.); (A.L.B.); (H.A.A.M.D.)
| | - Jochem Louisse
- Wageningen Food Safety Research (WFSR), 6708 WB Wageningen, The Netherlands; (J.L.); (A.P.)
| | - Ad Peijnenburg
- Wageningen Food Safety Research (WFSR), 6708 WB Wageningen, The Netherlands; (J.L.); (A.P.)
| | - Sophie Ndaw
- Institut National de Recherche et de Sécurité (INRS), 54500 Vandoeuvre-Lés-Nancy, France;
| | - Alberto Mantovani
- Istituto Superiore di Sanità (ISS), 00161 Rome, Italy; (A.M.); (B.D.S.)
| | - Barbara De Santis
- Istituto Superiore di Sanità (ISS), 00161 Rome, Italy; (A.M.); (B.D.S.)
| | - Marcel J. B. Mengelers
- Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands;
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Zhang YM. Orosomucoid-like protein 3, rhinovirus and asthma. World J Crit Care Med 2021; 10:170-182. [PMID: 34616654 PMCID: PMC8462028 DOI: 10.5492/wjccm.v10.i5.170] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/16/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
The genetic variants of orosomucoid-like protein 3 (ORMDL3) gene are associated with highly significant increases in the number of human rhinovirus (HRV)-induced wheezing episodes in children. Recent investigations have been focused on the mechanisms of ORMDL3 in rhinovirus infection for asthma and asthma exacerbations. ORMDL3 not only regulates major human rhinovirus receptor intercellular adhesion molecule 1 expression, but also plays pivotal roles in viral infection through metabolisms of ceramide and sphingosine-1-phosphate, endoplasmic reticulum (ER) stress, ER-Golgi interface and glycolysis. Research on the roles of ORMDL3 in HRV infection will lead us to identify new biomarkers and novel therapeutic targets in childhood asthma and viral induced asthma exacerbations.
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Affiliation(s)
- You-Ming Zhang
- Section of Genomic and Environmental Medicine, National Heart and Lung Institute, Molecular Genetics Group, Division of Respiratory Sciences, Imperial College London, London SW3 6LY, United Kingdom
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Kim SJ, Miller B, Mehta HH, Xiao J, Wan J, Arpawong TE, Yen K, Cohen P. The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity. Physiol Rep 2020; 7:e14171. [PMID: 31293078 PMCID: PMC6640593 DOI: 10.14814/phy2.14171] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 06/19/2019] [Accepted: 06/20/2019] [Indexed: 12/16/2022] Open
Abstract
MOTS‐c is an exercise mimetic and improves insulin sensitivity in aged and diet‐induced obese mice. Although plasma markers are good markers for the metabolic condition, whether MOTS‐c changes plasma markers in diet‐induced obese mice has not been examined. Here, we used an unbiased metabolomics approach to examine the effect of MOTS‐c on plasma markers of metabolic dysfunction. We found that three pathways – sphingolipid metabolism, monoacylglycerol metabolism, and dicarboxylate metabolism – were reduced in MOTS‐c–injected mice. Interestingly, these pathways are upregulated in obese and T2D models. MOTS‐c improves insulin sensitivity and increases beta‐oxidation to prevent fat accumulation in DIO mice through these pathways. These results provide us a better understanding of the mechanism of how MOTS‐c improves insulin sensitivity and reduces the body weight and fatty liver and opens a new venue for further study.
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Affiliation(s)
- Su-Jeong Kim
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA
| | - Brendan Miller
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA
| | - Hemal H Mehta
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA
| | - Jialin Xiao
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA
| | - Junxiang Wan
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA
| | - Thalida E Arpawong
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA
| | - Kelvin Yen
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA
| | - Pinchas Cohen
- Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA
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Li Y, Lu Z, Ru JH, Lopes-Virella MF, Lyons TJ, Huang Y. Saturated fatty acid combined with lipopolysaccharide stimulates a strong inflammatory response in hepatocytes in vivo and in vitro. Am J Physiol Endocrinol Metab 2018; 315:E745-E757. [PMID: 29989851 PMCID: PMC6293169 DOI: 10.1152/ajpendo.00015.2018] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and consumption of high-fat diet (HFD) is a risk factor for NAFLD. The HFD not only increases intake of saturated fatty acid (SFA) but also induces metabolic endotoxemia, an HFD-associated increase in circulating lipopolysaccharide (LPS). Although it is known that SFA or LPS promote hepatic inflammation, a hallmark of NAFLD, it remains unclear how SFA in combination with LPS stimulates host inflammatory response in hepatocytes. In this study, we performed both in vivo and in vitro experiments to investigate the effect of SFA in combination with LPS on proinflammatory gene expression in hepatocytes. Our animal study showed that feeding low-density lipoprotein-deficient mice HFD enriched with SFA and injection of low-dose LPS cooperatively stimulated IL-6 expression in livers. To understand how SFA and LPS interact to promote IL-6 expression, our in vitro studies showed that palmitic acid (PA), a major SFA, and LPS exerted synergistic effect on the expression of IL-6 in hepatocytes. Furthermore, coculture of hepatocytes with macrophages resulted in a greater IL-6 expression than culture of hepatocytes without macrophages in response to the combination of PA and LPS. Finally, we observed that LPS and PA increased ceramide production by cooperatively stimulating ceramide de novo synthesis, which played an essential role in the synergistic stimulation of proinflammatory gene expression by LPS and PA. Taken together, this study showed that SFA in combination with LPS stimulated a strong inflammatory response in hepatocytes in vivo and in vitro.
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Affiliation(s)
- Yanchun Li
- Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, College of Medicine Medical University of South Carolina, South Carolina
| | - Zhongyang Lu
- Ralph H. Johnson Veterans Affairs Medical Center , Charleston, South Carolina
| | - Ji Hyun Ru
- Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, College of Medicine Medical University of South Carolina, South Carolina
| | - Maria F Lopes-Virella
- Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, College of Medicine Medical University of South Carolina, South Carolina
- Ralph H. Johnson Veterans Affairs Medical Center , Charleston, South Carolina
| | - Timothy J Lyons
- Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, College of Medicine Medical University of South Carolina, South Carolina
| | - Yan Huang
- Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, College of Medicine Medical University of South Carolina, South Carolina
- Ralph H. Johnson Veterans Affairs Medical Center , Charleston, South Carolina
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Babenko NA, Shevereva VM, Gar’kavenko VV. Changes in the Sphingolipid Content in Tissues and Behavioral Modifications of Rats Subjected to Neurogenic Stress: Role of Sphingomyelinases. NEUROPHYSIOLOGY+ 2017. [DOI: 10.1007/s11062-017-9615-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Kulkarni H, Mamtani M, Blangero J, Curran JE. Lipidomics in the Study of Hypertension in Metabolic Syndrome. Curr Hypertens Rep 2017; 19:7. [PMID: 28168678 DOI: 10.1007/s11906-017-0705-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Mota M, Banini BA, Cazanave SC, Sanyal AJ. Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease. Metabolism 2016; 65:1049-61. [PMID: 26997538 PMCID: PMC4931958 DOI: 10.1016/j.metabol.2016.02.014] [Citation(s) in RCA: 384] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 02/05/2016] [Accepted: 02/23/2016] [Indexed: 12/21/2022]
Abstract
The exposure of hepatocytes to high concentrations of lipids and carbohydrates and the ensuing hepatocellular injury are termed lipotoxicity and glucotoxicity, respectively. A common denominator is metabolic derangement, especially in regards to intracellular energy homeostasis, which is brought on by glucose intolerance and insulin resistance in tissues. In this review, we highlight the lipids and carbohydrates that provoke hepatocyte injury and the mechanisms involved in lipotoxicity and glucotoxicity, including endoplasmic reticulum stress, oxidative stress and mitochondrial impairment. Through upregulation of proteins involved in various pathways including PKR-like ER kinase (PERK), CCAAT/enhancer-binding homologous protein (CHOP), c-Jun NH2-terminal kinase-1 (JNK), Bcl-2 interacting mediator (BIM), p53 upregulated modulator of apoptosis (PUMA), and eventually caspases, hepatocytes in lipotoxic states ultimately undergo apoptosis. The protective role of certain lipids and possible targets for pharmacological therapy are explored. Finally, we discuss the role of high fructose and glucose diets in contributing to organelle impairment and poor glucose transport mechanisms, which perpetuate hyperglycemia and hyperlipidemia by shunting of excess carbohydrates into lipogenesis.
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Affiliation(s)
- Manoela Mota
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
| | - Bubu A Banini
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Sophie C Cazanave
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Arun J Sanyal
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
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Babenko NA, Kharchenko VS. Modulation of Insulin Sensitivity of Hepatocytes by the Pharmacological Downregulation of Phospholipase D. Int J Endocrinol 2015; 2015:794838. [PMID: 26089893 PMCID: PMC4458285 DOI: 10.1155/2015/794838] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 04/30/2015] [Accepted: 05/11/2015] [Indexed: 12/13/2022] Open
Abstract
Background. The role of phospholipase D (PLD) as a positive modulator of glucose uptake activation by insulin in muscle and adipose cells has been demonstrated. The role of PLD in the regulation of glucose metabolism by insulin in the primary hepatocytes has been determined in this study. Methods. For this purpose, we studied effects of inhibitors of PLD on glucose uptake and glycogen synthesis stimulation by insulin. To determine the PLD activity, the method based on determination of products of transphosphatidylation reaction, phosphatidylethanol or phosphatidylbutanol, was used. Results. Inhibition of PLD by a general antagonist (1-butanol) or specific inhibitor, halopemide, or N-hexanoylsphingosine, or by cellular ceramides accumulated in doxorubicin-treated hepatocytes decreased insulin-stimulated glucose metabolism. Doxorubicin-induced hepatocytes resistance to insulin action could be abolished by inhibition of ceramide production. Halopemide could nullify this effect. Addition of propranolol, as well as inhibitors of phosphatidylinositol 3-kinase (PI3-kinase) (wortmannin, LY294002) or suppressors of Akt phosphorylation/activity, luteolin-7-O-glucoside or apigenin-7-O-glucoside, to the culture media could block cell response to insulin action. Conclusion. PLD plays an important role in the insulin signaling in the hepatocytes. PLD is activated downstream of PI3-kinase and Akt and is highly sensitive to ceramide content in the liver cells.
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Affiliation(s)
- Nataliya A. Babenko
- Department of Physiology of Ontogenesis, Biology Research Institute, Karazin Kharkov National University, Svobody Square 4, Kharkov 61022, Ukraine
- *Nataliya A. Babenko:
| | - Vitalina S. Kharchenko
- Department of Physiology of Ontogenesis, Biology Research Institute, Karazin Kharkov National University, Svobody Square 4, Kharkov 61022, Ukraine
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