Abstract
Nonalcoholic steatohepatitis (NASH) is characterized by hepatocyte injury and inflammatory cell infiltration, which has been linked to peripheral insulin resistance and increased levels of triglycerides in the liver. The purposes of this study were to establish a mouse model of NASH by feeding mice a 60% high-fat diet (HFD) and to demonstrate the anti-fibrotic effects of oleuropein, which has been shown to have anti-oxidant and anti-inflammatory properties, in this HFD-induced mouse model of NASH. C57BL/6 mice were divided into three groups: a regular diet group (Chow), a HFD group and an oleuropein-supplemented HFD group (OSD), which was fed a 0.05% OSD for 6 months. The effects of oleuropein in this model were evaluated using biochemical, histological and molecular markers. The expression levels of alpha-smooth muscle actin (α-SMA)and collagen type I in the HFD and OSD groups were evaluated using real-time PCR and western blotting. The body weight, biochemical marker levels, nonalcoholic fatty liver disease activity score, homeostasis model of assessment-insulin resistance (HOMA-IR) and leptin levels observed in the HFD group at 9 and 12 months were higher than those observed in the Chow group. The HOMA-IR and leptin levels in the OSD group were decreased compared with the HFD group. In addition, α-SMA and collagen type I expression were decreased by oleuropein treatment. We established a NASH model induced by HFD and demonstrated that this model exhibits the histopathological features of NASH progressing to fibrosis. Our results suggest that oleuropein may be pharmacologically useful in preventing the progression of steatohepatitis and fibrosis and may be a promising agent for the treatment of NASH in humans.
Highlights
nonalcoholic fatty liver disease (NAFLD) is associated with a wide spectrum of liver pathogenesis, from simple hepatic steatosis to cirrhosis and nonalcoholic steatohepatitis (NASH), and a subset of NAFLD can progress to hepatocellular carcinoma.[2,3]
Numerous attempts have been made to generate an animal model of NASH induced by genetic mutations, pharmacological manipulations and/or diet, and the histopathological features and the pathophysiology of NASH have been successfully demonstrated in several mouse and rat models of NASH induced by a high-fat diet (HFD).[7,8,9]
Liver index and biochemical values from serum and liver tissues TC, TG, free fatty acids (FFAs), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values in serum, and the body weights and liver indices for the regular diet (Chow) and HFD groups were investigated over the course of 12 months (Table 1)
Summary
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, and its prevalence has increased worldwide because of the over-nutrition that is common in the typical contemporary diet and the widespread lack of physical exercise.[1,2] NAFLD is associated with a wide spectrum of liver pathogenesis, from simple hepatic steatosis to cirrhosis and nonalcoholic steatohepatitis (NASH), and a subset of NAFLD can progress to hepatocellular carcinoma.[2,3] NASH is characterized by hepatocyte injury and inflammatory cell infiltration, which has been linked to peripheral insulin resistance and increased triglyceride (TG) concentrations in the liver.[4]. Oleuropein, a secoiridoid derived from olives (Olea europaea), can form a part of a healthy diet, and it is a component of several medicines.[9] The pharmacological properties of oleuropein include anti-oxidant, antiinflammatory, anti-atherogenic, anticancer, anti-microbial, anti-viral and anti-aging effects, and this phenolic compound has been suggested to exert therapeutic effects against coronary heart disease, Parkinson’s disease and Alzheimer’s disease.[8] Lipid metabolism in the liver, body fat accumulation and the plasma concentrations of free fatty acids (FFAs), leptin, and TGs were significantly decreased in rats treated with oleuropein.[12] Recently, we reported that oleuropein exhibits preventative and therapeutic effects in hepatic steatosis These effects have been associated with lipogenesis (that is, Wnt10b and FGFR1) and pro-inflammatory (TLR2 and TLR4) signaling pathways in a mouse model of NAFLD.[13]. The purposes of this study were to establish an experimental model of NASH by feeding mice a HFD and to evaluate the pharmacological effects of oleuropein in this model
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