| Nonalcoholic fatty liver disease (NAFLD) is characterized by diffuse hepatocyte steatosis. It includes nonalcoholic simple steatosis (NASFL), nonalcoholic steatohepatitis (NASH) and cirrhosis. Recently, NAFLD has become a new trouble with the higher incidence. Although generally a benign, indolent process, it can progress to advanced liver disease in approximately 15-20% of patients. NASH is the middle stage and rate-limiting step between NASFL and cirrhosis. So it is very important to block this process, and people pay much more effort to research on the pathogenesis of NAFLD now.Mosmann introduced the classification of CD4+T cell (T helper cell, Th) in 1986. Since then, people pay a close attention to the role of Th1/Th2 imbalance in autoimmune diseases, tumor and inflammatory diseases. CD4+ CD25+Regulatory T cells (Treg) play a major role in modulating the immune response. Foxp3 is the characteristic marker of Treg. But now there are few reports about the CD4+T polarization and Treg expression in the liver with NAFLD. As liver itself is an important immune organ, the relationship between Th1/Th2, Treg and chronic liver diseases has attracted researchers'attention. So we treated the SD rats with long-term high fat diet to set up NAFLD model, then to detect the gene expression of proinflammatory cytokine tumor necrosis factor-alpha (TNF-a), interferon-gamma (IFN-γ), anti-inflammatory cytokine interleukin-4 (IL-4) and Foxp3 in the liver with NAFLD, and then we expored the role of Th1/Th2 and Treg in NAFLD according to the datas. The results showed that long-term high fat diet could evoke the rats to develop NAFLD. We found that TNF-αwas increased slightly, but without statistical significance (P> 0.05). Foxp3 was significantly reduced (P> 0.05). IFN-γ, IL-4 had no significant change compared with the normal group (P>0.05). In NASH, Both of IFN-γand TNF-αwere increased significantly (P<0.05). IL-4 was not significantly different from the normal group (P>0.05). Foxp3 was decreased dramatically compared with both normal group and NASFL group (P<0.05). It indicates that the normal rats which fed with long-trem high fat diet can develop fatty livers, and hepatic immune system abnormalities including decreased Foxp3 and Treg in livers. The degradation of the inhibition functions of Treg, promotes CD4+T cells more polarized to Th1 with excessive IFN-γand TNF-αproduction. All of that promote the development of NAFLD.Liver is the metabolic center of body. fatty metabolic disorder and fatty accumulation cause hepatic steatosis. So in the second part we explored the metabonomic profile of NASH with metabonomic technology, and hope to find some clue. We found that there were significantly different metabonomic patterns in liver tissues between NASH group and normal group. Compared with the normal group, the fatty acid and amino acid spectrum displayed obvious changes in NASH model group. (1) Fatty acid analysis showed that the content dodecanoic acid was reduced significantly in NASH group (P<0.05). Octadecanoic acid,tetradecanoic acid,hexadecanoic acid,eicosanoic acid,9-octadecenoic acid,9,12,15-Octadecatrienoic acid,5,8,11,14-Eicosatetraenoic acid and 9,12-Octadecadienoic acid were increased dramatically in NASH group (P<0.05). Moreover,ω-6/ω-3 polyunsaturated fatty acids (PUFAs) ratio is raised. (2) Amino acid analysis showed that the contents of alanine, fumaric acid, aspartic acid, aminobutyric acid, glutamic acid, leucine, praline, succinic acid, glutamine and hydroxyproline were significantly decreased in NASH liver tissue (P<0.05). Glutamic acid and glutamine were found to have the most significant reduction. In addition, phenylalanine and tryptophan were slightly raised (P>0.05), valine and isoleucine were decreased slightly, but there was no statistical significance (P>0.05). The results suggest that there are significant fatty acid and amino acid metabolism changes in NASH. Excessive fatty acids accumulation in hepatic cells,ω-6/ω-3 ratio imbalance, dodecanoic acid decreased, and some amino acids contents changes are related to hepatic inflammation and injury. More interesting, the lower level of amino acids make us to think of cytokine COP-1, a copolymer of four amino acids(glutamic acid, lysine, alanine, tyrosine), which can stimulate the production of Foxp3, promote the transformation of CD4+CD25+T regulatory cells, and the processes above mainly depend on the large amount of IFN-γ. This may partially explains the possible mechanism of immune abnormality and the development of NAFLD induced by long-term high fat diet.
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