We have to keep in mind that NAFLD is part of a syndrome strongly overlapping with obesity and insulin resistance and therefore it seems likely that common genetic aspects AZD1152-HQPA mw for all those diseases exist. Whereas genetic factors overall may play a minor role in the current epidemic of obesity, certain genetic factors might well offer explanations for a more progressive disease course in NAFLD. NAFLD is a complex disease with no simple answers. Presented data, however, suggest that extrahepatic tissues could play an important role in the evolution of liver inflammation. Before advancing toward therapeutic

human studies, e.g., interfering with our microbiota, more information on the natural history of this disease is needed. Human studies investigating www.selleckchem.com/products/Y-27632.html the microbiota/microbiome should be initiated to define

whether there exists a “NASH-associated” (core) microbiome.106 To support our hypothesis, tissue-specific knockout animal models (adipose-specific, epithelial-specific, and macrophage-specific knockout mice) with special emphasis on mediators directing innate immune processes are needed. Interbreeding these mice will enable experiments to prove that “a defect” at both levels could induce a more inflammatory and progressive disease phenotype. Obesity and related disorders including NAFLD are the consequence of our current lifestyle and therefore “inflammatory” diets such as those rich in trans fatty acids and/or fructose, diets that activate the AhR, or others have to be investigated in various animal models to better define the “major triggers” in our diet. Based on our hypothesis, various potential treatment targets may evolve and treatment approaches beyond focusing on insulin resistance might be important. There might also be a need for combination therapies targeting various pathways in the disease process. A good example is vitamin E which as been recently demonstrated to show certain efficacy in the treatment of NASH.107 Interestingly, treatment with

vitamin E did not affect insulin resistance, suggesting that improvement in NASH may take place independent Urease of interference with insulin resistance. This is of interest because at least certain animal models suggest that presence of insulin resistance might accelerate steatohepatitis and degree of fibrosis.108 Because vitamin E suppresses proinflammatory cytokines and induces adiponectin, regulation of such key mediators in the disease process might be of considerable importance.109 Interference with ER stress might be another treatment option in the future. Chemical chaperones such as ursodeoxycholic acid (UCDA) reduced ER stress and improved metabolic functions in a mouse model of diabetes.