title: Polyunsaturated fatty acid metabolites as novel lipidomic biomarkers for noninvasive diagnosis of nonalcoholic steatohepatitis.
abstract: Lipotoxicity is a key mechanism thought to be responsible for the progression of nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH). Noninvasive diagnosis of NASH is a major unmet clinical need, and we hypothesized that PUFA metabolites, in particular arachidonic acid (AA)-derived eicosanoids, in plasma would differentiate patients with NAFL from those with NASH. Therefore, we aimed to assess the differences in the plasma eicosanoid lipidomic profile between patients with biopsy-proven NAFL versus NASH versus normal controls without nonalcoholic fatty liver disease (NAFLD; based on MRI fat fraction <5%). We carried out a cross-sectional analysis of a prospective nested case-control study including 10 patients with biopsy-proven NAFL, 9 patients with biopsy-proven NASH, and 10 non-NAFLD MRI-phenotyped normal controls. We quantitatively compared plasma eicosanoid and other PUFA metabolite levels between NAFL versus NASH versus normal controls. Utilizing a uniquely well-characterized cohort, we demonstrated that plasma eicosanoid and other PUFA metabolite profiling can differentiate between NAFL and NASH. The top candidate as a single biomarker for differentiating NAFL from NASH was 11,12-dihydroxy-eicosatrienoic acid (11,12-diHETrE) with an area under the receiver operating characteristic curve (AUROC) of 1. In addition, we also found a panel including 13,14-dihydro-15-keto prostaglandin D2 (dhk PGD2) and 20-carboxy arachidonic acid (20-COOH AA) that demonstrated an AUROC of 1. This proof-of-concept study provides early evidence that 11,12-diHETrE, dhk PGD2, and 20-COOH AA are the leading eicosanoid candidate biomarkers for the noninvasive diagnosis of NASH.
authors.affiliation: NAFLD Translational Research Unit, Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, CA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Loomba
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, CA Department of Medicine, University of California at San Diego, La Jolla, CA.
authors.forename: Oswald
authors.initials: O
authors.lastname: Quehenberger
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, CA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Armando
authors.affiliation: Department of Pharmacology, University of California at San Diego, La Jolla, CA Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D016022:Case-Control Studies; D015777:Eicosanoids / Q000097:blood / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000175:diagnosis* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype
chemical_list: D015415:Biomarkers; D015777:Eicosanoids
keywords: cirrhosis; diagnostic test accuracy; eicosanoid profiling; hepatic steatosis; liver disease; mass spectrometry; nonalcoholic fatty liver disease