MD-2 is an important component of LPS recognition; however, it may, or may not, be implicated in the recognition of the entire repertoire of TLR4 ligands. Alternatively, TLR4 with or without MD-2 may signal differently, or TLR4-MD-2 complex receptor may function in two separate modes: one in which full signaling occurs and one limited to MyD88-dependent ZD1839 signaling (13). We had previously reported a critical role of TLRs and the common TLR adaptor, MyD88, in other models of liver inflammation and injury (39); the exact signaling events downstream from TLR4-MD-2 complex in NASH are yet to be fully understood. Nevertheless, it is important to note that both TLR4 KO and MD-2 KO genotypes offered only partial protection against MCD diet-induced NASH, suggesting the possibility that TLR4/MD-2-independent events may be involved in the pathogenesis of NASH.
In conclusion, we found that danger receptor TLR4 and its coreceptor, MD-2, are critical in the development of steatosis, liver damage, inflammation, and fibrosis in the MCD diet-induced NASH in mice. The significant attenuation of steatohepatitis and the protection from fibrosis in the presence of MD-2 or TLR4 deficiency suggest that danger signals provided by MD-2-TLR4 complex play a central role in this model of NASH. GRANTS This work was supported by National Institutes of Health Grants 1R01DK-075635 (to G. Szabo) and 1R01AI-51405 (to E. Kurt-Jones), Public Health Service Grant DK-32520, and UMass CFAR Grant 5P30 AI-42845. DISCLOSURES No conflicts of interest are declared by the authors. ACKNOWLEDGMENTS We thank Dr. K.
Miyake (Division of Infectious Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan) for providing the KO animals. Current address for I. Hritz: 2nd Department of Medicine, Semmelweis University, Budapest, Hungary.
Hepatocellular carcinoma is a sequel of chronic liver disease and shows high and increasing prevalence worldwide. In most cases it is associated with the presence of liver cirrhosis and has a poor prognosis with an overall median survival of 8 months in Austria . To assess the survival of patients with hepatocellular carcinoma different prognostic models have been developed [2-5]. Although no staging system has emerged as standard, one of the most widely used survival model is the BCLC (Barcelona Clinic Liver Cancer) staging system  which appears to be the most comprehensive, as it links staging to treatment .
Treatment options which aim to obtain clinical cure include liver resection, liver transplantation and various forms of local ablation, such as percutaneous ethanol injection (PEI) or radiofrequency ablation. These treatment modalities are only available Batimastat for patients with early stage hepatocellular carcinomas (patients with BCLC stage A and B).