Significantly fewer Ki67- and pH3-positive hepatocytes CP868596 were detectable in Mdr2-/-c-MycΔ/Δ mice and regain of liver weight was significantly delayed. Similarly, Mdr2-/-c-MycΔ/Δ hepato-cytes transplanted into Fah-/—mice failed to repopulate the livers compared to c-Myc WT hepatocyte. Mechanistically, we provide evidence that c-Myc is required to maintain metabolic homeostasis in hepatocytes during chronic liver injury. Mechanistically, we provide evidence that loss of c-Myc significantly impaired oxidative phosphorylation in isolated hepatocytes. Accordingly, ATP levels were significantly

lower in Mdr2-/-c-MycΔ/Δ hepatocytes and the ATP/ADP ratio increased in Mdr2-/-c-MycΔ/Δ. Gene expression analysis identified several networks that were regulated by c-Myc including cellular assembly/organization, growth/proliferation Selleckchem FDA-approved Drug Library and inflammatory response. Together, we provide evidence that c-Myc is a central regulator of liver homeostasis in mice with chronic liver injury in contrast to the only modest phenotype of WT mice with a deletion of c-Myc in liver. C-Myc is specifically required to prevent

liver injury and induce liver regeneration in mice with pre-existing chronic liver injury. Disclosures: Michael P. Manns – Consulting: Roche, BMS, Gilead, Boehringer Ingelheim, Novartis, Idenix, Achillion, GSK, Merck/MSD, Janssen, Medgenics; Grant/ Research Support: Merck/MSD, Roche, Gilead, Novartis, Boehringer Ingelheim, BMS; Speaking and Teaching: Merck/MSD, Roche, BMS, Gilead, Janssen, GSK, Novartis The following people have nothing to disclose: Stephanie Klett, Kristin Hanak, Bruno Guigas, Robert Geffers, Jessica Endig, Laura E. Buitrago, Silke Marhenke, Arndt Vogel Background: TIGAR is a bisphosphatase that has been linked to the inhibition of glycolysis and increased carbohydrate flux through the pentose-phosphate shunt (PPS). A PPS intermediate, xylulose-5-phosphate (X5P) has

been shown to suppress AKT phosphorylation by activating protein phosphatase 2A (PP2A). Increased AKT phosphorylation has been demonstrated to be an important determinant of sorafenib resistance in hepato-cellular carcinoma (HCC) cells. Hypothesis: Overexpression of TIGAR may improve chemosensitivity in sorafenib-resistant Molecular motor HCC cells by inhibiting glycolysis, and promoting the formation of X5P that subsequently leads to diminished AKT phos-phorylation via PP2A activation. Methods: HepG2, Hep3B, FOCUS and HepaRG HCC cell lines were employed in this study to assess the correlation between AKT phosphorylation and TIGAR expression/chemosensitivity. Full-length human TIGAR cDNA was overexpressed in cells with low endogenous TIGAR levels (HepaRG and FOCUS). Overexpression was confirmed by real-time PCR, Western-blotting, subcellular localization studies, and biochemical assays. Cellular X5P content was assessed by HPLC-MS/MS. AKT phosphorylation was measured by Western-blotting.