Metabolite profiling identifies anandamide as a biomarker of nonalcoholic steatohepatitis.

The discovery of metabolite-phenotype associations may highlight candidate biomarkers and metabolic pathways altered in disease states. We sought to identify novel metabolites associated with obesity and one of its major complications, nonalcoholic fatty liver disease (NAFLD), using a liquid chromatography-tandem mass spectrometry method. In 997 individuals in Framingham Heart Study Generation 3 (FHS Gen 3), we identified an association between anandamide (AEA) and BMI. Further examination revealed that AEA was associated with radiographic hepatic steatosis. In a histologically defined NAFLD cohort, AEA was associated with NAFLD severity, the presence of nonalcoholic steatohepatitis, and fibrosis. These data highlight AEA as a marker linking cardiometabolic disease and NAFLD severity.

[1]  D. Levy,et al.  Bi-directional analysis between fatty liver and cardiovascular disease risk factors. , 2017, Journal of hepatology.

[2]  Z. Halpern,et al.  Serum levels of endocannabinoids are independently associated with nonalcoholic fatty liver disease , 2017, Obesity.

[3]  E. Guallar,et al.  Persistent Nonalcoholic Fatty Liver Disease Increases Risk for Carotid Atherosclerosis. , 2016, Gastroenterology.

[4]  A. Ward,et al.  Lipid Abundance in Zebrafish Embryos Is Regulated by Complementary Actions of the Endocannabinoid System and Retinoic Acid Pathway. , 2015, Endocrinology.

[5]  Tom R. Gaunt,et al.  Metabolite profiling and cardiovascular event risk: a prospective study of 3 population-based cohorts. , 2015, Circulation.

[6]  H. Yki-Järvinen Non-alcoholic fatty liver disease as a cause and a consequence of metabolic syndrome. , 2014, The lancet. Diabetes & endocrinology.

[7]  R. Vasan,et al.  2-Aminoadipic acid is a biomarker for diabetes risk. , 2013, The Journal of clinical investigation.

[8]  K. Furie,et al.  Metabolite Profiling Identifies a Branched Chain Amino Acid Signature in Acute Cardioembolic Stroke , 2013, Stroke.

[9]  C. Silvestri,et al.  The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. , 2013, Cell metabolism.

[10]  Terho Lehtimäki,et al.  Branched-Chain and Aromatic Amino Acids Are Predictors of Insulin Resistance in Young Adults , 2013, Diabetes Care.

[11]  A. Peters,et al.  Identification of Serum Metabolites Associated With Risk of Type 2 Diabetes Using a Targeted Metabolomic Approach , 2013, Diabetes.

[12]  G. Her,et al.  Cannabinoid receptor 1 promotes hepatic lipid accumulation and lipotoxicity through the induction of SREBP-1c expression in zebrafish , 2013, Transgenic Research.

[13]  Christian Gieger,et al.  Novel biomarkers for pre-diabetes identified by metabolomics , 2012, Molecular systems biology.

[14]  K. Cusi,et al.  The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association , 2012, The American Journal of Gastroenterology.

[15]  Susan Cheng,et al.  Metabolite Profiling Identifies Pathways Associated With Metabolic Risk in Humans , 2012, Circulation.

[16]  J. Asara,et al.  A positive/negative ion–switching, targeted mass spectrometry–based metabolomics platform for bodily fluids, cells, and fresh and fixed tissue , 2012, Nature Protocols.

[17]  Giorgio Saracco,et al.  The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: An international collaborative study , 2011, Hepatology.

[18]  C. Gieger,et al.  Human metabolic individuality in biomedical and pharmaceutical research , 2011, Nature.

[19]  Joshua D. Knowles,et al.  Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry , 2011, Nature Protocols.

[20]  S. Carr,et al.  Lipid profiling identifies a triacylglycerol signature of insulin resistance and improves diabetes prediction in humans. , 2011, The Journal of clinical investigation.

[21]  V. Mootha,et al.  Metabolite profiles and the risk of developing diabetes , 2011, Nature Medicine.

[22]  Deepak L. Bhatt,et al.  Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial , 2010, The Lancet.

[23]  S. Ambudkar,et al.  Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. , 2010, The Journal of clinical investigation.

[24]  A. Seymour,et al.  High-throughput and multiplexed LC/MS/MRM method for targeted metabolomics. , 2010, Analytical chemistry.

[25]  S. Klein,et al.  Obesity and nonalcoholic fatty liver disease: Biochemical, metabolic, and clinical implications , 2010, Hepatology.

[26]  E. Brunt,et al.  Nonalcoholic fatty liver disease: pathology and pathogenesis. , 2010, Annual review of pathology.

[27]  R. Capasso,et al.  Peripheral endocannabinoid dysregulation in obesity: relation to intestinal motility and energy processing induced by food deprivation and re‐feeding , 2009, British journal of pharmacology.

[28]  Svati H Shah,et al.  A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. , 2009, Cell metabolism.

[29]  V. Marzo,et al.  Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors , 2009, Diabetologia.

[30]  J. Hirschhorn,et al.  Liver fat is reproducibly measured using computed tomography in the Framingham Heart Study , 2008, Journal of gastroenterology and hepatology.

[31]  R. Capasso,et al.  Dysregulation of peripheral endocannabinoid levels in hyperglycemia and obesity: Effect of high fat diets , 2008, Molecular and Cellular Endocrinology.

[32]  Douglas B. Kell,et al.  Statistical strategies for avoiding false discoveries in metabolomics and related experiments , 2007, Metabolomics.

[33]  M. Fasshauer,et al.  Dysregulation of the Peripheral and Adipose Tissue Endocannabinoid System in Human Abdominal Obesity , 2006, Diabetes.

[34]  Wenyun Lu,et al.  Separation and quantitation of water soluble cellular metabolites by hydrophilic interaction chromatography-tandem mass spectrometry. , 2006, Journal of chromatography. A.

[35]  M. Maj,et al.  Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. , 2006, The Journal of clinical endocrinology and metabolism.

[36]  F Xavier Pi-Sunyer,et al.  Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. , 2006, JAMA.

[37]  J. Després,et al.  Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. , 2005, The New England journal of medicine.

[38]  O. Cummings,et al.  Design and validation of a histological scoring system for nonalcoholic fatty liver disease , 2005, Hepatology.

[39]  K. Mackie,et al.  Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. , 2005, The Journal of clinical investigation.

[40]  B. Neuschwander‐Tetri,et al.  Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis , 2020, Clinical Gastroenterology and Hepatology.

[41]  C. Flachskamm,et al.  The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. , 2003, The Journal of clinical investigation.

[42]  T. Annesley Ion suppression in mass spectrometry. , 2003, Clinical chemistry.

[43]  G. Marchesini,et al.  Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome , 2003, Hepatology.

[44]  R. Palmiter,et al.  Leptin-regulated endocannabinoids are involved in maintaining food intake , 2001, Nature.

[45]  E. Ellis,et al.  The biodisposition and metabolism of anandamide in mice. , 1997, The Journal of pharmacology and experimental therapeutics.

[46]  P. Smith,et al.  The pharmacological activity of anandamide, a putative endogenous cannabinoid, in mice. , 1994, The Journal of pharmacology and experimental therapeutics.

[47]  Gerald van Belle,et al.  Sample Size as a Function of Coefficient of Variation and Ratio of Means , 1993 .

[48]  G. Reaven,et al.  Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. , 1991, JAMA.

[49]  M. Mann,et al.  Electrospray Ionization for Mass Spectrometry of Large Biomolecules , 1990 .