title: Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: new evidence on the potential therapeutic mechanism.
abstract: Pentoxifylline (PTX) improved the histological features of nonalcoholic steatohepatitis (NASH) in a recent randomized placebo-controlled trial. However, the underlying mechanism responsible for the beneficial effects of PTX in NASH remains unidentified. A key role of lipid oxidation in the pathogenesis and progression of NASH has been established. PTX is known to decrease free-radical-mediated oxidative stress and inhibit lipid oxidation. The primary aim of this study was to evaluate the effects of PTX on levels of lipid oxidation products in patients with NASH. Levels of multiple structurally specific oxidized fatty acids including hydroxy-octadecadienoic acids (HODEs), oxo-octadecadienoic acids (oxoODEs), and hydroxy-eicosatetraenoic acids (HETEs) were quantified by mass spectrometry in plasma obtained at baseline and at study completion in patients who completed 1 year of therapy with PTX or placebo in a randomized controlled trial. Therapy with PTX resulted in significant decreases in 9-HODE and 13-oxoODE, oxidized lipid products of linoleic acid (LA) linked to histological severity in nonalcoholic fatty liver disease. Similarly, PTX therapy was associated with significant decreases in 8-HETE, 9-HETE, and 11-HETE compared to placebo. Statistically significant correlations were demonstrated between the decrease in HODEs and oxoODEs and improved histological scores of fibrosis and between the decrease in HETEs and improved lobular inflammation.
  
  
  CONCLUSIONS
  Therapy with PTX compared to placebo was associated with a significant reduction of oxidized fatty acids. This novel evidence supports that the beneficial effects of PTX in patients with NASH are likely partly mediated through decreasing lipid oxidation, largely free-radical-mediated lipid oxidation. Additionally, this is the first report on the link between decreased oxidized lipid products and improved histological disease in the setting of a therapeutic trial in NASH.
authors.affiliation: Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44915, USA. zeinc@ccf.org
authors.forename: Claudia O
authors.initials: CO
authors.lastname: Zein
authors.forename: Rocio
authors.initials: R
authors.lastname: Lopez
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Fu
authors.forename: John P
authors.initials: JP
authors.lastname: Kirwan
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Yerian
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: McCullough
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Feldstein
mesh_terms: D000328:Adult; D001707:Biopsy, Needle; D001774:Blood Chemical Analysis; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005234:Fatty Liver / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D007333:Insulin Resistance; D019787:Linoleic Acid / Q000097:blood; D050356:Lipid Metabolism / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D065626:Non-alcoholic Fatty Liver Disease; D018579:Patient Selection; D010431:Pentoxifylline / Q000008:administration & dosage*; D011446:Prospective Studies; D012016:Reference Values; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D016896:Treatment Outcome
chemical_list: D019787:Linoleic Acid; D010431:Pentoxifylline