Project Summary Hepatic steatosis is the most common emerging liver disease occurring in the US population, and is caused by an abnormal accumulation of lipids within hepatocytes. The Liver X receptor alpha (LXR) is a major transcription factor for regulating the genes promoting de novo lipogenesis, specifically biosynthesis of fatty acids (FAs) and triglycerides (TGs), which contributes to hepatic steatosis. Recent studies from my laboratory suggest that Nogo-B receptor (NgBR) plays a previously unrecognized role in regulating LXRnuclear translocation. Our new findings support the concept that NgBR inhibits nuclear translocation of LXR and that NgBR expression is essential for preventing LXRdependent lipogenesis. However, the molecular mechanisms by which NgBR regulates LXR translocation remain unknown. This proposal is designed to fill gaps in our knowledge concerning the role of NgBR in regulating LXR translocation, and to determine if blocking LXR nuclear translocation is sufficient to prevent hepatic steatosis. Preliminary results show that NgBR expression is decreased in fatty livers, and NgBR hepatocyte-specific knockout (hepKO) mice have increased FA and TG content in the liver. These data suggest that a decrease in NgBR expression induces LXR nuclear translocation, which lead to hepatic steatosis. Based on these findings and previous reports, we hypothesize that NgBR regulates LXRα nuclear translocation in hepatocytes through the LKB1-AMPK pathway, and disruption of this regulation leads to hepatic steatosis. Our overall objectives are to elucidate the molecular mechanisms by which NgBR prevents LXR nuclear translocation and the roles NgBR plays in the pathogenesis of hepatic steatosis. Delineating the mechanisms by which NgBR regulates LXR nuclear translocation will allow us to develop new therapeutic strategies for preventing hepatic steatosis. Accordingly, we will test our hypothesis in the three specific aims. Aim 1: Determine the roles of NgBR-LKB1 interaction in regulating AMPK activation. Aim 2: Determine the molecular mechanism by which the NgBR- LKB1-AMPK pathway regulates LXRα phosphorylation and nuclear translocation. Aim 3: Determine the roles NgBR plays in the pathogenesis of hepatic steatosis and steatohepatitis; and, determine the extent to which preventing LXR nuclear translocation ameliorates hepatic steatosis. The proposed studies will reveal new therapeutic strategies for preventing and/or reducing hepatic steatosis and thus have a significant impact on the field of hepatology. If successful, we will be the first to show how NgBR signaling regulates the molecular mechanisms driving hepatic steatosis. Our studies will lead to new discoveries that will greatly improve the health of US citizens and others suffering from hepatic steatosis. Our studies will reveal new concepts and ideas that can be used to develop therapies for treating hepatic steatosis. Accordingly, the translational potential of this applic...