Pentoxifylline decreases oxidized lipid products in nonalcoholic steatohepatitis: New evidence on the potential therapeutic mechanism

Authors


  • Potential conflict of interest: Dr. Hazen reports being listed as coinventor on pending and issued patents held by the Cleveland Clinic relating to diagnostics. Dr. Hazen reports having been paid as a consultant or speaker for the following companies: Abbott, Cleveland Heart Lab, Esperion, Lilly, Liposcience Inc., Merck & Co., Inc., and Pfizer Inc. Dr. Hazen reports receiving research funds from Abbott, Cleveland Heart Lab, Esperion, Liposcience Inc., and Pfizer Inc. Dr. Hazen reports having the right to receive royalty payments for inventions or discoveries related to diagnostics or therapeutics from: Abbott, Cleveland Heart Lab., Esperion, Frantz Biomarkers, LLC, Liposcience Inc., and Siemens.

  • Dr. Claudia Zein is supported by Grant Number KL2 RR024990 from the National Center for Research Resources (NCRR) and the National Center for Advancing Translational Sciences, National Institutes of Health, components of the NIH and NIH Roadmap for Medical Research. This project was supported by the American College of Gastroenterology Junior Faculty Career Development Award to Dr. Zein; and Grant Number M01 RR00080 and Grant Number UL1 RR024989 from the National Center for Research Resources (NCRR) and the National Center for Advancing Translational Sciences, National Institutes of Health. Oxidized lipid analyses were supported by grant PO1HL076491 to Dr. Hazen. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.

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. Conclusion: 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. (HEPATOLOGY 2012)

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