It was previously reported that SREBP1c, a key regulator of fatty acid synthesis, is implicated in the development of fatty liver. Intriguingly, we found that the expression levels of SREBP1c as well as the critical lipogenic genes controlled by SREBP1c were all upregulated by ethanol treatment and by Smad7 deletion. These results not only indicate that SREBP1c pathway is involved in ethanol-induced hepatic steatosis, but also suggest that Smad7 deletion may aggravate fatty liver formation through upregulation of SREBP1c. We also analyzed hepatic expression of a series of proinflammatory cytokines and chemokines. We found that chemokines and a number of proinflammatory cytokines were significantly increased by ethanol feeding in wild type mice, confirming that ethanol is able to successfully induced inflammatory response in the liver. We also found that Smad7 deletion led to significant increase of chemokines and proinflammatory cytokines. The Smad7liver-KO mice with high efficiency of Smad7 deletion had Bortezomib Proteasome inhibitor spontaneous liver dysfunction, demonstrated as general deterioration of the body condition and increased serum levels of AST and ALT, accompanied by liver degeneration and an increase in hepatocyte apoptosis. Furthermore, hepatic injury and steatosis induced by chronic alcohol exposure were accelerated by Smad7 deletion. These data, therefore, reveal for the first time that loss of endogenous Smad7 in the liver can result in spontaneous liver dysfunction and SCH727965 enhance ethanolinduced liver injury. Our results are consistent with a few recent studies pinpointing the functional role of Smad7 in liver diseases. Overexpression of Smad7 in mouse liver could attenuate TGF-b signaling and TGF-b-induced EMT, while improve CCl4-provoked liver fibrosis. On the other hand, hypomorphic Smad7 deficiency could enhance CCl4-induced liver damage and fibrosis. The liver damage imposed by Smad7 deletion as observed in this study and by Hamzavi, et al is likely mediated by hyperactivity of TGF-b signaling, as overexpression of TGF-b1 specifically in mouse liver leads to increases in hepatic fibrosis and hepatocyte apoptosis. However, unlike this study, spontaneous liver dysfunction was not observed with hypomorphic Smad7 deficiency.We speculate that the difference is dependent on themagnitude of Smad7 deletion. Deletion of theMH1 domain of Smad7 gene only leads to partial loss of Smad7 function. In our study, we found that spontaneous liver dysfunction only occur in Smad7liver-KO mice with high degree of Smad7 deletion. It is speculated that the function of Smad7 needs to be lost to certain degree to initiate spontaneous liver damage in the mouse. TGF-b is considered one of the most important growth factors that induce EMT process.