Loomba Rohit, Quehenberger Oswald, Armando Aaron, Dennis Edward A
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.
Department of Pharmacology, University of California at San Diego, La Jolla, CA Department of Medicine, University of California at San Diego, La Jolla, CA.
J Lipid Res. 2015 Jan;56(1):185-92. doi: 10.1194/jlr.P055640. Epub 2014 Nov 17.
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.
脂毒性是一种关键机制，被认为是非酒精性脂肪肝（NAFL）进展为非酒精性脂肪性肝炎（NASH）的原因。NASH的无创诊断是一项尚未满足的主要临床需求，我们推测血浆中的多不饱和脂肪酸（PUFA）代谢物，特别是花生四烯酸（AA）衍生的类二十烷酸，能够区分NAFL患者和NASH患者。因此，我们旨在评估经活检证实的NAFL患者、NASH患者与无非酒精性脂肪性肝病（NAFLD；基于MRI脂肪分数<5%）的正常对照者之间血浆类二十烷酸脂质组学谱的差异。我们对一项前瞻性巢式病例对照研究进行了横断面分析，该研究包括10例经活检证实的NAFL患者、9例经活检证实的NASH患者和10例经MRI表型分析的非NAFLD正常对照者。我们定量比较了NAFL患者、NASH患者与正常对照者之间血浆类二十烷酸和其他PUFA代谢物水平。利用一个特征独特且充分的队列，我们证明血浆类二十烷酸和其他PUFA代谢物谱能够区分NAFL和NASH。作为区分NAFL和NASH的单一生物标志物的首要候选物是11,12-二羟基-二十碳三烯酸（11,12-diHETrE），其受试者工作特征曲线下面积（AUROC）为1。此外，我们还发现一个包括13,14-二氢-15-酮前列腺素D2（dhk PGD2）和20-羧基花生四烯酸（20-COOH AA）的组合，其AUROC为1。这项概念验证研究提供了早期证据，表明11,12-diHETrE、dhk PGD2和20-COOH AA是NASH无创诊断的主要类二十烷酸候选生物标志物。
