Thymosin alpha 1 attenuates lipid peroxidation and improves fructose-induced steatohepatitis in rats
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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2017, Journal of Molecular LiquidsCitation Excerpt :High fructose potentiates protein fructosylation and the formation of reactive oxygen species (ROS) in the liver [93]. High fructose diet induces steatosis, inflammation and periportal fibrosis [45,94,95]. High fructose diet induces histopathological changes that is associated with dyslipidaemia, insulin resistance, elevated pro-inflammatory cytokines and markers of lipid peroxidation [30] in rats.