The low-grade or chronic inflammation in NAFLD and insulin resistance resulting from lipid accumulation in liver

The liver is an important principal organ in the maintenance of glucose homeostasis and energy storage for the conversion of excess dietary nutrients into triglycerides. Under HFD feeding conditions, excess TG in the liver induces fatty liver and eventually insulin resistance. HFD feeding increased the body weight gradually along the time course, 2 weeks after HFD. HFD rats body weight was significantly higher edna techniques efficient inventory monitoring programs sensitive species compared to NCD rats, and FX treatment tended to decrease the body weight although not significantly. The weight of various tissues, including SCF, EF, and pancreas, was similar amongst all groups. The liver weight and relative liver weight in FX treated rats were significantly lower than that of HFD rats, suggesting that FX has a beneficial effect on lowering TG content in the liver. It has been shown that FX has hepatotoxicity at a high dosage, while the doses we used here didn’t induce a further alteration of serum ALT and AST level compared to rats on HFD alone. When administrated to normal chow diet rats, FX even tended to decrease the ALT levels, implying a potential liver protective effect. TG is thought to be a surrogate marker of disrupted insulin signal. In other words, hepatic insulin resistance is associated with the accumulation of TG and FA metabolites. The rate of glucose disposal and insulin sensitivity were measured by OGTT and IPITT. FX treated rats had significantly lower levels of blood glucose after administration of an exogenous load of glucose, suggesting an enhanced glucose disposal. When challenged with excessive amounts of insulin, FX treatment showed drastically reduced level of blood glucose and improved glucose disposal in HFD rats, suggesting that FX increased insulin sensitivity. The raised insulin sensitivity could also reflect less lipid accumulation in the liver indirectly. FX treatment significantly decreased liver TG content. Morphologically, the liver of HFD rats showed abundant and large lipid droplets, and obvious increase of liver derangement compared to that of NCD rats. However, the liver of FX rats had fewer lipid droplets and more normal liver morphology, suggesting a beneficial effect of FX on preventing lipid accumulation and reversal of disrupted structure of the liver. In addition, FX may also exert liver protective effect via inhibition of HFDinduced inflammation, since our results showed that FX decreased gene expression of inflammatory cytokines. To explore the possible mechanisms of FX on decreasing liver lipids accumulation, we investigated the expression levels of several genes related to fatty acid transport, and lipid metabolism including lipogenesis and b-oxidation. ChREBP regulates the balance between glycogen and triglyceride storage by coordinately regulating glycolytic and lipogenic gene expression. The results showed that the level of ChREBP was significantly higher in the liver of rats fed HFD compared with that of NCD. FX effectively inhibited the raise of ChREBP expression. Expression of ChREBP transcriptional targets FAS and ACC1 also strongly correlates with ChREBP expression. FAS catalyze the last step in fatty acid biosynthesis, and thus, it is believed to be a major determinant of the maximal hepatic capacity to generate fatty acids by de novo lipogenesis. FX markedly decreased the HFD-induced high expression of ACC1 and FAS. The trend of SCD1 influenced by FX was similar to that of FAS but only at high dose. There is evidence suggested that transgenic hepatic over-expression of SREBP-1c produced a fatty liver and a 4-fold increase in the rate of hepatic fatty acid synthesis with increase in lipogenic genes like FAS, ACC, and SCD. Here, we showed that hepatic SREBP1c mRNA in HFD rats was increased. FX treatment generated a significant decreasing effect on its expression paralleled with the change in ChREBP expression.