Role of leptin on alcohol-induced oxidative stress in Swiss mice

Abstract

Previous studies suggest a possible link between leptin and hepatic inflammation; however, the role of leptin on liver disease remain unclear. The purpose of the present study was to evaluate the effect of leptin on tissue lipid peroxidation and the antioxidant status in experimental hepatotoxicity. Administering ethanol (6.32 g/kg body weight) to 4-week-old healthy mice for 45 days resulted in significantly elevated levels of tissue thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD) and lowered activities of superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathione related enzymes such as glutathione peroxidase (GPx) and glutathione S-transferase (GST) as compared with those of the control mice. subsequent to the experimental induction of hepatotoxicity (i.e. after the initial period of 30 days) exogenous leptin was simultaneously administered (230 μg/kg body weight) every alternate day for 15 days along with the daily dose of alcohol. Leptin administration to control and alcohol-treated mice significantly reduced the weight gain, significantly elevated the liver and kidney levels of TBARS and CD, and significantly lowered the levels of enzymic and non-enzymic antioxidants as compared with the untreated control and alcohol supplemented mice. It is postulated that the increase in systemic leptin levels enhance the oxidative stress, and lower the antioxidant defence, leading to augmented hepatic inflammation in alcoholic liver disease.

Introduction

Lipid peroxidation mediated by free radicals is considered to be a primary mechanism of cell membrane destruction and cell damage [1]. One of the most thoroughly investigated examples is the lipid peroxidation stimulated by the model hepatotoxin-ethanol. There appears to be increasing evidence that alcohol toxicity may be associated with increased oxidative stress and free radical associated injury [2]. Generation of oxygen metabolites such as superoxide (O₂⁻) hydrogen peroxide (H₂O₂) and hydroxyl radicals (OH⁻) is believed to be important in the pathogenesis of alcoholic liver injury [3]. To counteract these oxidants, cells have several antioxidant enzymes including superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT).

Leptin is a 167-amino acid cytokine-like peptide, synthesized by adipocytes and secreted into the blood stream. Administration of leptin to ob/ob mice lowered their body weight, percent body fat and food intake as well as enhanced their energy expenditure. These effects strongly implicated leptin as a negative feed back signal, which reflects body adiposity by acting at the hypothalamic level [4].

Recently, it was reported that leptin is produced not only by adipose tissues but also by other tissues, including stomach [5]. Interestingly, isolated hepatic stellate cells have been shown to produce leptin during the in vitro transactivation process [6]. Further, it has been reported that serum leptin levels are increased in patients with alcohol-induced cirrhosis [7], [8]. These observations suggested a possible involvement of leptin in the pathogenesis of liver diseases. Moreover, clinical studies have disclosed that obesity is a risk factor for the progression of chronic liver diseases including viral hepatitis [9], alcohol-induced liver disease [10], and non-alcoholic steato hepatitis [11]. Although obese people show obvious hyperleptinemia [12], it is still unclear whether an increase in systemic leptin levels is involved in the progression of liver diseases. In the present study, therefore, we evaluated the effect of administering exogenous leptin on tissue lipid peroxidation and the enzymic and non-enzymic antioxidants in alcohol-induced liver injury in mice.