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. 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).
Article: Improved Hepatic Lipid Composition Following Short-Term Exercise in Non-Alcoholic Fatty Liver Disease.[show abstract] [hide abstract]
ABSTRACT: Context:Hepatic steatosis, insulin resistance, inflammation, low levels of polyunsaturated lipids, and adiponectin are implicated in the development and progression of non-alcoholic fatty liver disease (NAFLD).Objective:We examined the effects of short-term aerobic exercise on these metabolic risk factors.Design and Participants:Obese individuals (N=17, 34.3±1.0 kg/m(2)) with clinically confirmed NAFLD were enrolled in a short-term aerobic exercise program that consisted of 7 consecutive days of treadmill walking at ∼85% of HRmax for 60 min/d. Pre- and post-intervention measures included hepatic triglyceride content, and a lipid saturation index (SI) and polyunsaturated lipid index (PUI) of the liver, obtained by (1)H magnetic resonance (MR) spectroscopy (N=14). Insulin sensitivity was estimated from an oral glucose tolerance test (OGTT), and mononuclear cells were isolated to assess reactive oxygen species (ROS) production during the OGTT. Circulating glucose, insulin, and high molecular weight (HMW) adiponectin were determined from plasma.Main Outcome:Short-term aerobic exercise training improved hepatic lipid composition in patients with NAFLD.Results:Exercise training resulted in an increase in liver PUI (P<0.05), increased insulin sensitivity (Matsuda Index: P<0.05), HMW adiponectin (P<0.05), and VO2max (P<0.05). ROS production during the OGTT was reduced following exercise training (P<0.05). HMW adiponectin was increased after the exercise program and the increase was positively correlated with the increase in liver PUI (r=0.52, P=0.05). Body weight remained stable during the program (P>0.05).Conclusion:Short-term exercise can target hepatic lipid composition, which may reduce the risk of NAFLD progression. The improvement in hepatic lipid composition may be driven by adiponectin.The Journal of clinical endocrinology and metabolism 04/2013; · 6.50 Impact Factor
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ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world (it affects 30% of the general adult population). The NAFLD encompasses a histological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), defined by steatosis, hepatocellular damage, and lobular inflammation in individuals without significant alcohol consumption and negative viral, congenital, and autoimmune liver disease markers. Currently, NAFLD is considered an emerging epidemic in light of the dramatic increase in obesity rates. With the progressive nature of NASH and its rising prevalence there is a significant need for a specific and targeted treatments since to date there has not been any validated therapies for NAFLD other than weight loss, which is well known to have a poor long-term success rate. In recent years, visceral adipose tissue has taken an important role in NAFLD pathogenesis, and current therapeutic approaches aim at reducing visceral obesity and free fatty acid overflow to the liver. This paper is focused on the treatments used for NAFLD and the potential new therapy.International journal of hepatology. 01/2012; 2012:464706.