Abstract 17811: A Metabolomics Platform Optimized for Human Plasma Identifies Anandamide as a Biomarker of Nonalcoholic Steatohepatitis

Introduction: Quantification of metabolites in plasma samples can highlight important metabolic pathways that are altered in disease states. Hypothesis: We developed a metabolomics approach to identify novel biomarkers of cardiometabolic traits in a large community-based cohort. Methods: Using liquid chromatography-tandem mass spectrometry, we developed a metabolite profiling method that minimizes pre-analytical sample processing and uses Amide Xbridge chromatography to separate and detect positively and negatively charged metabolites across a broad spectrum of chemical classes. We applied this method to 1,000 participants in the Framingham Heart Study Generation 3 cohort (mean age 40 years, 53% women) to identify novel metabolic alterations present in obesity and its complications. Regression analyses were performed with adjustment for age and sex. Results: We identified multiple novel associations of metabolites with cardiometabolic traits, including the endogenous cannabinoid, anandamide, which was associated with body mass index (p=3.64x10 -13 ), glucose (p=1.08x10 -6 ), homeostatic model assessment of insulin resistance (p=2.10x10 -7 ) and systolic blood pressure (p=1.95x10 -9 ). In follow-up studies in a hospital-based sample (N=72) of patients with obesity, higher plasma anandamide levels were independently associated with histologically-defined nonalcoholic steatohepatitis (OR 5.45, 95% CI 1.48-20.1, p=0.01), an obesity complication that must otherwise be diagnosed by liver biopsy. Conclusion: Our observations highlight both the role of anandamide in obesity and nonalcoholic steatohepatitis, and the utility of metabolomics-based approaches for illuminating novel markers of disease and metabolic dysregulation.