Background & AimsNonalcoholic steatohepatitis (NASH) is characterized by steatosis, lobular inflammation, hepatocyte ballooning with fibrosis in severe cases and high prevalence in obesity. We aimed at defining NASH signature in morbid obesity by mass spectrometry-based lipidomic analysis.MethodsSystemic blood before and 12 months post bariatric surgery along with portal blood and adipose tissue lipid efflux collected at the time of surgery from obese women were analyzed (9 structural classes, 150 species).ResultsIncreased concentrations of several Glycerophosphocholines (PC), Glycerophosphoethanolamines (PE), Glycerophosphoinositols (PI), Glycerophosphoglycerols (PG), Lyso-Glycerophosphocholines (LPC), and Ceramides (Cer) were detected in systemic circulation of NASH subjects. Weight loss post-surgery (12 months) improved the levels of liver enzymes, as well as several lipids, but most PG and Cer species remained elevated. Analysis of lipids from hepatic portal system at the time of surgery revealed limited lipid alterations compared to systemic circulation, but PG and PE classes were found significantly increased in NASH subjects. We evaluated the contribution of visceral adipose tissue to lipid alterations in portal circulation by measuring adipose tissue lipid efflux ex vivo, which demonstrated only minor alterations in NASH subjects. Interestingly, integration of clinical and lipidomic data (portal and systemic) led us to define a NASH signature in which lipids and clinical parameters are equal contributorsConclusionCirculatory (portal and systemic) phospholipid profiling and clinical data defines NASH signature in morbid obesity. We report weak contribution of visceral adipose tissue to NASH-related portal lipid alterations, suggesting possible contribution from other organs draining into hepatic portal system.