title: Mass spectrometric profiling of oxidized lipid products in human nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.
abstract: Oxidative stress is a core abnormality responsible for disease progression in nonalcoholic fatty liver disease (NAFLD). However, the pathways that contribute to oxidative damage in vivo are poorly understood. Our aims were to define the circulating profile of lipid oxidation products in NAFLD patients, the source of these products, and assess whether their circulating levels reflect histological changes in the liver. The levels of multiple structurally specific oxidized fatty acids, including individual hydroxy-eicosatetraenoic acids (HETE), hydroxy-octadecadenoic acids (HODE), and oxo-octadecadenoic acids (oxoODE), were measured by mass spectrometry in plasma at time of liver biopsy in an initial cohort of 73 and a validation cohort of 49 consecutive patients. Of the markers monitored, 9- and 13-HODEs and 9- and 13-oxoODEs, products of free radical-mediated oxidation of linoleic acid (LA), were significantly elevated in patients with nonalcoholic steatohepatitis (NASH), compared with patients with steatosis. A strong correlation was revealed between these oxidation products and liver histopathology (inflammation, fibrosis, and steatosis). Further analyses of HODEs showed equivalent R and S chiral distribution. A risk score for NASH (oxNASH) was developed in the initial clinical cohort and shown to have high diagnostic accuracy for NASH versus steatosis in the independent validation cohort. Subjects with elevated oxNASH levels (top tertile) were 9.7-fold (P < 0.0001) more likely to have NASH than those with low levels (bottom tertile). Collectively, these findings support a key role for free radical-mediated linoleic acid oxidation in human NASH and define a risk score, oxNASH, for noninvasive detection of the presence of NASH.
authors.affiliation: Department of Cell Biology, Cleveland Clinic College of Medicine, Case Western Reserve University, Cleveland, OH, USA. feldsta@ccf.org
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Feldstein
authors.forename: Rocio
authors.initials: R
authors.lastname: Lopez
authors.forename: Tarek Abu-Rajab
authors.initials: TA
authors.lastname: Tamimi
authors.forename: Lisa
authors.initials: L
authors.lastname: Yerian
authors.forename: Yoon-Mi
authors.initials: YM
authors.lastname: Chung
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.forename: Renliang
authors.initials: R
authors.lastname: Zhang
authors.forename: Thomas M
authors.initials: TM
authors.lastname: McIntyre
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D015331:Cohort Studies; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000737:chemistry / Q000378:metabolism; D019787:Linoleic Acid / Q000737:chemistry / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood* / Q000737:chemistry; D065626:Non-alcoholic Fatty Liver Disease; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*
chemical_list: D005231:Fatty Acids, Unsaturated; D006893:Hydroxyeicosatetraenoic Acids; D008055:Lipids; C027369:octadecadienoic acid; D019787:Linoleic Acid