Abstract
Prevention of hepatic fat accumulation may be an important approach for liver diseases due to the increased relevance of hepatic steatosis in this field. This study was conducted to investigate the effects of the antioxidant α-lipoic acid (α-LA) on hepatic steatosis, hepatocellular function, and oxidative stress in a model of type 2 diabetes fed with a high fat diet (HFD). Goto-Kakizaki rats were randomly divided into four groups. The first group received only a standard rat diet (control GK) including groups 2 (HFD), 3 (vehicle group), and 4 (α-LA group), which were given HFD, ad libitum during three months. Wistar rats are the non-diabetic control group. Carbohydrate and lipid metabolism, liver function, plasma and liver tissue malondialdehyde (MDA), liver GSH, tumor necrosis factor-α (TNF-α) and nuclear factor E2 (erythroid-derived 2)-related factor-2 (Nrf2) levels were assessed in the different groups. Liver function was assessed using quantitative hepatobiliary scintigraphy, serum aspartate, and alanine aminotransferases (AST, ALT), alkaline phosphatase, gamma-glutamyltranspeptidase, and bilirubin levels. Histopathologically steatosis and fibrosis were evaluated. Type 2 diabetic animals fed with HFD showed a marked hepatic steatosis and a diminished hepatic extraction fraction and both were fully prevented with α-LA. Plasma and liver tissue MDA and hepatic TNF-α levels were significantly higher in the HFD group when compared with the control group and significantly lower in the α-LA group. Systemic and hepatic cholesterol, triglycerides, and serum uric acid levels were higher in hyperlipidemic GK rats and fully prevented with α-LA. In addition, nuclear Nrf2 activity was significantly diminished in GK rats and significantly augmented after α-LA treatment. In conclusion, α-LA strikingly ameliorates steatosis in this animal model of diabetes fed with HFD by decrementing the inflammatory marker TNF-α and reducing oxidative stress. α-LA might be considered a useful therapeutic tool to prevent hepatic steatosis by incrementing antioxidant defense systems through Nrf2 and consequently decreasing oxidative stress and inflammation in type 2 diabetes.
Highlights
Liver steatosis is frequently observed in conditions such as obesity and diabetes [1]
Based on studies in animal models, it was previously described that lipid peroxidation is one of the mechanisms that could promote the progression from steatosis to steatohepatitis, which is a process characterized by inflammation [1,2]
Livers from the GK rats fed with high fat diet (HFD) were significantly greater in size compared to control GK rats and significantly smaller in the α-lipoic acid (α-LA)-treated GK rats compared to the GK fed with HFD
Summary
Liver steatosis (fatty liver) is frequently observed in conditions such as obesity and diabetes [1]. Often considered as a benign condition, steatosis may evolve to steatohepatitis and even to cirrhosis. Lipid peroxidation has been implicated in non-alcoholic steatohepatitis (NASH). Based on studies in animal models, it was previously described that lipid peroxidation is one of the mechanisms that could promote the progression from steatosis to steatohepatitis, which is a process characterized by inflammation [1,2]. Lipid peroxidation can be demonstrated in steatosis but progression of steatosis to steatohepatitis in humans is not a constant feature, which implies the requirement of other factors in the pathogenesis of this process [3]. It has been previously shown that a high-fat diet (HFD), insulin resistance, inflammation, and oxidative stress are considered important in the pathogenesis of human NASH [4,5]
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