Abstract
Individuals with anorexia nervosa (AN) restrict eating and become emaciated. They tend to have an aversion to foods rich in fat. Because epoxide hydrolase 2 (EPHX2) was identified as a novel AN susceptibility gene, and because its protein product, soluble epoxide hydrolase (sEH), converts bioactive epoxides of polyunsaturated fatty acid (PUFA) to the corresponding diols, lipidomic and metabolomic targets of EPHX2 were assessed to evaluate the biological functions of EPHX2 and their role in AN. Epoxide substrates of sEH and associated oxylipins were measured in ill AN, recovered AN and gender- and race-matched controls. PUFA and oxylipin markers were tested as potential biomarkers for AN. Oxylipin ratios were calculated as proxy markers of in vivo sEH activity. Several free- and total PUFAs were associated with AN diagnosis and with AN recovery. AN displayed elevated n-3 PUFAs and may differ from controls in PUFA elongation and desaturation processes. Cytochrome P450 pathway oxylipins from arachidonic acid, linoleic acid, alpha-linolenic acid and docosahexaenoic acid PUFAs are associated with AN diagnosis. The diol:epoxide ratios suggest the sEH activity is higher in AN compared with controls. Multivariate analysis illustrates normalization of lipidomic profiles in recovered ANs. EPHX2 influences AN risk through in vivo interaction with dietary PUFAs. PUFA composition and concentrations as well as sEH activity may contribute to the pathogenesis and prognosis of AN. Our data support the involvement of EPHX2-associated lipidomic and oxylipin dysregulations in AN, and reveal their potential as biomarkers to assess responsiveness to future intervention or treatment.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Smink FR, van Hoeken D, Hoek HW . Epidemiology of eating disorders: incidence, prevalence and mortality rates. Curr Psychiatry Rep 2012; 14: 406–414.
Arcelus J, Mitchell AJ, Wales J, Nielsen S . Mortality rates in patients with anorexia nervosa and other eating disorders. A meta-analysis of 36 studies. Arch Gen Psychiatry 2011; 68: 724–731.
Papadopoulos FC, Ekbom A, Brandt L, Ekselius L . Excess mortality, causes of death and prognostic factors in anorexia nervosa. Br J Psychiatry 2009; 194: 10–17.
Thornton LM, Mazzeo SE, Bulik CM . The heritability of eating disorders: methods and current findings. Curr Top Behav Neurosci 2011; 6: 141–156.
Fernstrom MH, Weltzin TE, Neuberger S, Srinivasagam N, Kaye WH . Twenty-four-hour food intake in patients with anorexia nervosa and in healthy control subjects. Biol Psychiatry 1994; 36: 696–702.
Drewnowski A, Pierce B, Halmi KA . Fat aversion in eating disorders. Appetite 1988; 10: 119–131.
Ruiz-Prieto I, Bolanos-Rios P, Jauregui-Lobera I . Diet choice in weight-restored patients with eating disorders; progressive autonomy process by nutritional education. Nutr Hosp 2013; 28: 1725–1731.
Jauregui Lobera I, Bolanos Rios P . Choice of diet in patients with anorexia nervosa. Nutr Hosp 2009; 24: 682–687.
Steinglass JE, Sysko R, Mayer L, Berner LA, Schebendach J, Wang Y et al. Pre-meal anxiety and food intake in anorexia nervosa. Appetite 2010; 55: 214–218.
Simopoulos AP . Essential fatty acids in health and chronic disease. Am J Clin Nutr 1999; 70: 560S–569S.
Uauy R, Dangour AD . Nutrition in brain development and aging: role of essential fatty acids. Nutr Rev 2006; 64: S24–S33, discussion S72-91.
Pelliccia F, Marazzi G, Greco C, Franzoni F, Speziale G, Gaudio C . Current evidence and future perspectives on n-3 PUFAs. Int J Cardiol 2013; 170: S3–S7.
Zak A, Vecka M, Tvrzicka E, Hruby M, Novak F, Papezova H et al. Composition of plasma fatty acids and non-cholesterol sterols in anorexia nervosa. Physiol Res 2005; 54: 443–451.
Squali Houssaini FZ, Foulon T, Payen N, Iraqi MR, Arnaud J, Groslambert P . Plasma fatty acid status in Moroccan children: increased lipid peroxidation and impaired polyunsaturated fatty acid metabolism in protein-calorie malnutrition. Biomed Pharmacother 2001; 55: 155–162.
Holman RT, Johnson SB, Mercuri O, Itarte HJ, Rodrigo MA, De Tomas ME . Essential fatty acid deficiency in malnourished children. Am J Clin Nutr 1981; 34: 1534–1539.
Holman RT, Adams CE, Nelson RA, Grater SJ, Jaskiewicz JA, Johnson SB et al. Patients with anorexia nervosa demonstrate deficiencies of selected essential fatty acids, compensatory changes in nonessential fatty acids and decreased fluidity of plasma lipids. J Nutr 1995; 125: 901–907.
Scott-Van Zeeland AA, Bloss CS, Tewhey R, Bansal V, Torkamani A, Libiger O et al. Evidence for the role of EPHX2 gene variants in anorexia nervosa. Mol Psychiatry 2014; 19: 724–732.
Newman JW, Morisseau C, Hammock BD . Epoxide hydrolases: their roles and interactions with lipid metabolism. Prog Lipid Res 2005; 44: 1–51.
Koeners MP, Wesseling S, Ulu A, Sepulveda RL, Morisseau C, Braam B et al. Soluble epoxide hydrolase in the generation and maintenance of high blood pressure in spontaneously hypertensive rats. Am J Physiol Endocrinol Metab 2011; 300: E691–E698.
Morisseau C, Sahdeo S, Cortopassi G, Hammock BD . Development of an HTS assay for EPHX2 phosphatase activity and screening of nontargeted libraries. Anal Biochem 2013; 434: 105–111.
Morisseau C, Hammock BD . Impact of soluble epoxide hydrolase and epoxyeicosanoids on human health. Annu Rev Pharmacol Toxicol 2013; 53: 37–58.
Morisseau C, Inceoglu B, Schmelzer K, Tsai HJ, Jinks SL, Hegedus CM et al. Naturally occurring monoepoxides of eicosapentaenoic acid and docosahexaenoic acid are bioactive antihyperalgesic lipids. J Lipid Res 2010; 51: 3481–3490.
Sura P, Sura R, Enayetallah AE, Grant DF . Distribution and expression of soluble epoxide hydrolase in human brain. J Histochem Cytochem 2008; 56: 551–559.
De Taeye BM, Morisseau C, Coyle J, Covington JW, Luria A, Yang J et al. Expression and regulation of soluble epoxide hydrolase in adipose tissue. Obesity (Silver Spring, Md) 2010; 18: 489–498.
Marowsky A, Burgener J, Falck JR, Fritschy JM, Arand M . Distribution of soluble and microsomal epoxide hydrolase in the mouse brain and its contribution to cerebral epoxyeicosatrienoic acid metabolism. Neuroscience 2009; 163: 646–661.
Pinheiro AP, Bulik CM, Thornton LM, Sullivan PF, Root TL, Bloss CS et al. Association study of 182 candidate genes in anorexia nervosa. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 1070–1080.
Bloss CS, Berrettini W, Bergen AW, Magistretti P, Duvvuri V, Strober M et al. Genetic association of recovery from eating disorders: the role of GABA receptor SNPs. Neuropsychopharmacology 2011; 36: 2222–2232.
First MB, Gibbon M, Spitzer RL, Williams JBW . Users guide for the structured clinical interview for DSM-IV Axis I disorders- research versio (SCID-I, version 2.0, February 1996 FINAL VERSION). Biometrics Research Department, New York State Psychiatric Institute: New York, 1996.
Quehenberger O, Armando AM, Dennis EA . High sensitivity quantitative lipidomics analysis of fatty acids in biological samples by gas chromatography-mass spectrometry. Biochim Biophys Acta 2011; 1811: 648–656.
Zivkovic AM, Yang J, Georgi K, Hegedus C, Nording ML, O'Sullivan A et al. Serum oxylipin profiles in IgA nephropathy patients reflect kidney functional alterations. Metabolomics 2012; 8: 1102–1113.
Yang J, Dong H, Hammock BD . Profiling the regulatory lipids: another systemic way to unveil the biological mystery. Curr Opin Lipidol 2011; 22: 197–203.
Yang J, Schmelzer K, Georgi K, Hammock BD . Quantitative profiling method for oxylipin metabolome by liquid chromatography electrospray ionization tandem mass spectrometry. Anal chem 2009; 81: 8085–8093.
Team RDC . R A language and environment for statistical computing. R Foundation for Statistical Computing: Vienna, Austria, 2011.
Yang J, Zhao X, Liu X, Wang C, Gao P, Wang J et al. High performance liquid chromatography-mass spectrometry for metabonomics: potential biomarkers for acute deterioration of liver function in chronic hepatitis B. J Proteome Res 2006; 5: 554–561.
Rigaud D, Tallonneau I, Verges B . Hypercholesterolaemia in anorexia nervosa: frequency and changes during refeeding. Diabetes Metab 2009; 35: 57–63.
Weinbrenner T, Zuger M, Jacoby GE, Herpertz S, Liedtke R, Sudhop T et al. Lipoprotein metabolism in patients with anorexia nervosa: a case-control study investigating the mechanisms leading to hypercholesterolaemia. Br J Nutr 2004; 91: 959–969.
Zhu P, Peck B, Licea-Perez H, Callahan JF, Booth-Genthe C . Development of a semi-automated LC/MS/MS method for the simultaneous quantitation of 14,15-epoxyeicosatrienoic acid, 14,15-dihydroxyeicosatrienoic acid, leukotoxin and leukotoxin diol in human plasma as biomarkers of soluble epoxide hydrolase activity in vivo. J Chromatogr B Analyt Technol Biomed Life Sci 2011; 879: 2487–2493.
Lee JP, Yang SH, Kim DK, Lee H, Kim B, Cho JY et al. In vivo activity of epoxide hydrolase according to sequence variation affects the progression of human IgA nephropathy. Am J Physiol Renal Physiol 2011; 300: F1283–F1290.
Bulik CM, Sullivan PF, Tozzi F, Furberg H, Lichtenstein P, Pedersen NL . Prevalence, heritability, and prospective risk factors for anorexia nervosa. Arch Gen Psychiatry 2006; 63: 305–312.
Karwautz AF, Wagner G, Waldherr K, Nader IW, Fernandez-Aranda F, Estivill X et al. Gene-environment interaction in anorexia nervosa: relevance of non-shared environment and the serotonin transporter gene. Mol Psychiatry 2011; 16: 590–592.
Hsu LK . Can dieting cause an eating disorder? Psychol Med 1997; 27: 509–513.
Isomaa R, Isomaa AL, Marttunen M, Kaltiala-Heino R, Bjorkqvist K . Psychological distress and risk for eating disorders in subgroups of dieters. Eur Eat Disord Rev 2010; 18: 296–303.
Wagner A, Barbarich-Marsteller NC, Frank GK, Bailer UF, Wonderlich SA, Crosby RD et al. Personality traits after recovery from eating disorders: do subtypes differ? Int J Eat Disord 2006; 39: 276–284.
Morisseau C . Role of epoxide hydrolases in lipid metabolism. Biochimie 2013; 95: 91–95.
Crawford MA, Doyle W, Leaf A, Leighfield M, Ghebremeskel K, Phylactos A . Nutrition and neurodevelopmental disorders. Nutr Health 1993; 9: 81–97.
Allen KL, Mori TA, Beilin L, Byrne SM, Hickling S, Oddy WH . Dietary intake in population-based adolescents: support for a relationship between eating disorder symptoms, low fatty acid intake and depressive symptoms. J Hum Nutr Diet 2012; 26: 459–469.
Swenne I, Rosling A . Omega-3 essential fatty acid status is improved during nutritional rehabilitation of adolescent girls with eating disorders and weight loss. Acta Paediatr 2012; 101: 858–861.
Caspar-Bauguil S, Montastier E, Galinon F, Frisch-Benarous D, Salvayre R, Ritz P . Anorexia nervosa patients display a deficit in membrane long chain poly-unsaturated fatty acids. Clin Nutr 2012; 31: 386–390.
Swenne I, Rosling A, Tengblad S, Vessby B . Omega-3 polyunsaturated essential fatty acids are associated with depression in adolescents with eating disorders and weight loss. Acta Paediatr 2011; 100: 1610–1615.
Swenne I, Rosling A, Tengblad S, Vessby B . Essential fatty acid status in teenage girls with eating disorders and weight loss. Acta Paediatrica 2011; 100: 762–767.
Langan SM, Farrell PM . Vitamin E, vitamin A and essential fatty acid status of patients hospitalized for anorexia nervosa. Am J Clin Nutr 1985; 41: 1054–1060.
Ayton AK, Azaz A, Horrobin DF . A pilot open case series of ethyl-EPA supplementation in the treatment of anorexia nervosa. Prostaglandins Leukot Essent Fatty Acids 2004; 71: 205–209.
Ayton AK, Azaz A, Horrobin DF . Rapid improvement of severe anorexia nervosa during treatment with ethyl-eicosapentaenoate and micronutrients. Eur Psychiatry 2004; 19: 317–319.
Catala A . Five Decades with Polyunsaturated Fatty Acids: Chemical Synthesis, Enzymatic Formation, Lipid Peroxidation and Its Biological Effects. J Lipids 2013; 2013: 710290.
Brenner RR . The oxidative desaturation of unsaturated fatty acids in animals. Mol Cell Biochem 1974; 3: 41–52.
Dacks PA, Shineman DW, Fillit HM . Current evidence for the clinical use of long-chain polyunsaturated n-3 fatty acids to prevent age-related cognitive decline and Alzheimer's disease. J Nutr Health Aging 2013; 17: 240–251.
Edwards R, Peet M, Shay J, Horrobin D . Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients. J Affect Disord 1998; 48: 149–155.
Syrbu SI, Waterman WH, Molski TF, Nagarkatti D, Hajjar JJ, Sha'afi RI . Phosphorylation of cytosolic phospholipase A2 and the release of arachidonic acid in human neutrophils. J Immunol 1999; 162: 2334–2340.
Diez E, Chilton FH, Stroup G, Mayer RJ, Winkler JD, Fonteh AN . Fatty acid and phospholipid selectivity of different phospholipase A2 enzymes studied by using a mammalian membrane as substrate. Biochem J 1994; 301 (Pt 3): 721–726.
Damsbo-Svendsen S, Ronsholdt MD, Lauritzen L . Fish oil-supplementation increases appetite in healthy adults. A randomized controlled cross-over trial. Appetite 2013; 66: 62–66.
Dellava JE, Kendler KS, Neale MC . Generalized anxiety disorder and anorexia nervosa: evidence of shared genetic variation. Depress Anxiety 2011; 28: 728–733.
Klump KL, Strober M, Bulik CM, Thornton L, Johnson C, Devlin B et al. Personality characteristics of women before and after recovery from an eating disorder. Psychol Med 2004; 34: 1407–1418.
Bailer UF, Frank GK, Price JC, Meltzer CC, Becker C, Mathis CA et al. Interaction between serotonin transporter and dopamine D2/D3 receptor radioligand measures is associated with harm avoidant symptoms in anorexia and bulimia nervosa. Psychiatry Res 2013; 211: 160–168.
Podolin PL, Bolognese BJ, Foley JF, Long E 3rd, Peck B, Umbrecht S et al. In vitro and in vivo characterization of a novel soluble epoxide hydrolase inhibitor. Prostaglandins Other Lipid Mediat 2013; 104-105: 25–31.
Przybyla-Zawislak BD, Srivastava PK, Vazquez-Matias J, Mohrenweiser HW, Maxwell JE, Hammock BD et al. Polymorphisms in human soluble epoxide hydrolase. Mol Pharmacol 2003; 64: 482–490.
Lee CR, North KE, Bray MS, Fornage M, Seubert JM, Newman JW et al. Genetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study. Hum Mol Genet 2006; 15: 1640–1649.
Lee CR, Pretorius M, Schuck RN, Burch LH, Bartlett J, Williams SM et al. Genetic variation in soluble epoxide hydrolase (EPHX2) is associated with forearm vasodilator responses in humans. Hypertension 2011; 57: 116–122.
Fava C, Montagnana M, Danese E, Almgren P, Hedblad B, Engstrom G et al. Homozygosity for the EPHX2 K55R polymorphism increases the long-term risk of ischemic stroke in men: a study in Swedes. Pharmacogenet Genomics 2010; 20: 94–103.
Fornage M, Boerwinkle E, Doris PA, Jacobs D, Liu K, Wong ND . Polymorphism of the soluble epoxide hydrolase is associated with coronary artery calcification in African-American subjects: The Coronary Artery Risk Development in Young Adults (CARDIA) study. Circulation 2004; 109: 335–339.
Wei Q, Doris PA, Pollizotto MV, Boerwinkle E, Jacobs DR Jr., Siscovick DS et al. Sequence variation in the soluble epoxide hydrolase gene and subclinical coronary atherosclerosis: interaction with cigarette smoking. Atherosclerosis 2007; 190: 26–34.
Ohtoshi K, Kaneto H, Node K, Nakamura Y, Shiraiwa T, Matsuhisa M et al. Association of soluble epoxide hydrolase gene polymorphism with insulin resistance in type 2 diabetic patients. Biochem Biophys Res Commun 2005; 331: 347–350.
Burdon KP, Lehtinen AB, Langefeld CD, Carr JJ, Rich SS, Freedman BI et al. Genetic analysis of the soluble epoxide hydrolase gene, EPHX2, in subclinical cardiovascular disease in the Diabetes Heart Study. Diab Vasc Dis Res 2008; 5: 128–134.
Gschwendtner A, Ripke S, Freilinger T, Lichtner P, Muller-Myhsok B, Wichmann HE et al. Genetic variation in soluble epoxide hydrolase (EPHX2) is associated with an increased risk of ischemic stroke in white Europeans. Stroke 2008; 39: 1593–1596.
Wutzler A, Kestler C, Perrot A, Loehr L, Huemer M, Parwani AS et al. Variations in the human soluble epoxide hydrolase gene and recurrence of atrial fibrillation after catheter ablation. Int J Cardiol 2013; 168: 3647–3651.
Ramirez CE, Shuey MM, Milne GL, Gilbert K, Hui N, Yu C et al. Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans. Prostaglandins Other Lipid Mediat 2014; 113-115: 38–44.
Li L . Association of MiRNA-146a polymorphism with risk of cardiovascular disease and ischemia stroke and the mechanisms. Master’s thesis, Central South University: China 2011.
Campbell IC, Mill J, Uher R, Schmidt U . Eating disorders, gene-environment interactions and epigenetics. Neurosci Biobehav Rev 2011; 35: 784–793.
University of Minnesota. Laboratory of Physiological Hygiene. University of Minnesota. Laboratory of Physiological Hygiene. Keys AB . The Biology of Human Starvation. University of Minnesota Press: Minneapolis, 1950.
Marzola E, Nasser J, Hashim S, Shih P, Kaye W . Nutritional Rehabilitation in Anorexia Nervosa: Implications for Treatment. BMC Psychiatry 2013; 13: 290.
Gorla K, Mathews M . Pharmacological treatment of eating disorders. Psychiatry (Edgmont) 2005; 2: 43–48.
Acknowledgements
This work was supported, in part, by National Institutes of Health (NIH/NIDDK) Career Development Award Grant (1K01DK087813-01A1—Shih); NIH West Coast Metabolomics Center Pilot Grant (Shih); Price Foundation of Geneva, Switzerland; NIH U24 DK097154/DK/NIDDK; NIEHS R01 ES002710 and NIEHS/Superfund Research Program P42 ES004699. We acknowledge the special help with PUFA data management provided by Yan Wang, and the Price Foundation study collaborators for providing the clinical data and biospecimens for this study.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Molecular Psychiatry website
Supplementary information
Rights and permissions
About this article
Cite this article
Shih, P., Yang, J., Morisseau, C. et al. Dysregulation of soluble epoxide hydrolase and lipidomic profiles in anorexia nervosa. Mol Psychiatry 21, 537–546 (2016). https://doi.org/10.1038/mp.2015.26
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2015.26
This article is cited by
-
Metabolomics signatures of acutely ill and short-term weight recovered women with anorexia nervosa
Molecular Psychiatry (2021)
-
PET imaging of soluble epoxide hydrolase in non-human primate brain with [18F]FNDP
EJNMMI Research (2020)
-
Very long chain fatty acids are an important marker of nutritional status in patients with anorexia nervosa: a case control study
BioPsychoSocial Medicine (2020)
-
An Overview of Conceptualizations of Eating Disorder Recovery, Recent Findings, and Future Directions
Current Psychiatry Reports (2018)
-
Emerging Treatments in Eating Disorders
Neurotherapeutics (2017)