Elsevier

Clinical Biochemistry

Volume 38, Issue 6, June 2005, Pages 540-547
Clinical Biochemistry

Thymosin alpha 1 attenuates lipid peroxidation and improves fructose-induced steatohepatitis in rats

https://doi.org/10.1016/j.clinbiochem.2005.01.013Get rights and content

Abstract

Objectives:

The aim of this study was to investigate the effects of thymosin α1 (Tα1) in rats having fructose-induced steatosis. Fructose leads to experimental steatosis in the liver by exerting its effect on some components of the oxidant/antioxidant system, and on several cytokines (interleukin-1β, -2, and -6) in blood.

Methods:

Twenty-four rats at random were divided into three groups (each group containing eight animals); the control group (C), which received a purified diet; the high-fructose-fed group (F); and the high-fructose-fed and Tα1 injected group (F + T). After the experimental period of 10 days, liver lipid peroxidation and antioxidant status, and blood IL-1β, IL-2, and IL-6 levels were quantified.

Results:

In comparison with the C group, the F group had a higher nitric oxide (NO) level, xanthine oxidase (XO) activity, and lipid peroxidation, as indicated by concentrations of thiobarbituric acid reactive substances (TBARS), and lower superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the liver. In the F + T group, these markers were near the values of the control group. In addition, increased IL-1β and IL-6 levels were kept at near to normal levels with treatment of Tα1, but not IL-2 levels. In the F group, the most consistent findings in the histologic sections of liver tissues were the macrovesicular and microvesicular steatosis. Tα1 treatment protected the majority of the liver cells, while minimal macrovesicular and microvesicular steatosis was observed in the remaining cells.

Conclusions:

These results show that a high-fructose diet in rats leads to hepatic steatosis and a defect in the free radical defense system, and that treatment of Tα1 may improve these biochemical and morphologic changes in the fructose-fed rat livers.

Introduction

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the two most common chronic liver diseases in the general population of the United States, with prevalences of 20% and 3%, respectively. NAFLD includes a wide spectrum of liver injury ranging from simple steatosis to steatohepatitis, fibrosis, and cirrhosis. Steatosis, which is characterized by intracellular accumulation of lipids in cytoplasmic vacuoles, represents the most common alteration found in the liver in the general population. It appears to be associated with oxidative events regardless of the specific cause [1], [2]. Evidence of an increased generation of reactive oxygen species (ROS) has been described in several animal models of fatty liver, including alcohol or caffeine administration; however, within a few days, the choline-deprived diet produces massive liver steatosis, predominantly macrovesicular, without evidence of inflammation and/or fibrosis [3], [4], [5]. Environmental factors, such as diets and toxins, can also deteriorate hepatic fatty acid synthesis and oxidation. Dietary fructose hepatic lipogenesis increases and exerts acute effects on hepatocyte energy homeostasis. When adult Wistar rats are given 10% fructose in the drinking water for 48 h, hepatic fatty acid synthase is induced and de novo fatty acid synthesis and esterification increase significantly [6], [7], [8]. The underlying mechanisms for the detrimental consequences of a high-fructose diet in animal models are not clear. However, the ability of fructose to induce peroxidation of membrane lipids is widely reviewed in the literature [9], [10]. In addition, lipid peroxidation is associated with inflammation and cytokine activation, thus increased ROS could cause more lipid peroxidation and induction of proinflammatory cytokines in hepatocytes [11], [12]. No therapy for NASH has been proven to be clearly effective. Currently, treatment of hepatic steatosis is focused on modifying risk factors such as obesity, diabetes mellitus, and hyperlipidemia. Thymosin alpha 1 (Tα1) is a hormone produced by thymic stromal cells that can augment host defense mechanisms by increasing the production of T cells by the thymus. It has been used in medicine for diagnosis and treatment of many diseases [13], [14]. Moreover, it has been shown to have immunomodulatory [15], antitumor [16], antioxidant [17], and wound healing [18] properties. The potential therapeutic efficacy of antioxidants in steatohepatitis is not yet clear. The aim of this study was to evaluate possible antioxidant and protective roles of Tα1 in prevention of fructose-induced hepatic steatosis.

Section snippets

Animals and experimental design

Male Wistar albino rats weighting 280–300 g were used in this study. The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). The animals were housed at 20–24°C with a 12-h light, 12-h dark cycle and supplied with standard rat chow freely available. Rats were randomly assigned to one of the three groups (each group containing eight animals); the control group (C), which

Biochemical findings

All the biochemical data are summarized in Table 1, Table 2. As shown in Table 2, the high-fructose diet induced remarkable hypertriglyceridemia in both liver and plasma in our experimental model. Fructose-induced steatosis was also confirmed histologically (Fig. 2). In the F group, the levels of triglyceride in the plasma and liver were significantly increased compared to the control group (P < 0.001). Increase in plasma and liver triglyceride levels was observed to be less in the Tα1 injected

Discussion

Nonalcoholic steatohepatitis (NASH) is one of the most common liver diseases encountered in the United States and Europe. Although this term refers to a spectrum of hepatic pathology that resembles alcoholic liver disease, it refers to a wide spectrum of liver damage, ranging from simple steatosis to steatohepatitis, advanced fibrosis, and cirrhosis [2]. A ‘two-hit’ concept of disease pathogenesis has been proposed. The first hit is steatosis, and this is postulated to sensitize the liver to

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