Thus, we generated double knockout (DKO) mice without p62 (a gene to regulate food intake) or Nrf2 (a transcription factor to regulate anti-oxi-dative stress genes). Objective: We analyzed the pathological characteristics of liver tissue specimens to determine whether DKO mice exhibit steatohepatitis. To confirm a hypothesis for bacteria-induced metabolic liver disease (Diabetes 2008), we focused on the
intestines, adipose tissue and the disturbance of in vivo clearance of lipopolysaccharide (LPS) in the mice. Methods: Using both WT and DKO mice, we performed histological analyses of liver, intestine and adipose tissue learn more to examine pathological characteristics. Since Kupffer cells (KCs) provide the predominant protection against the influx of LPS, we determined KC phagocytic function by examining super-paramagnetic iron oxide (SPIO)-enhanced MR images. SPIO is a well-known contrast agent that is selectively incorporated by KCs after intravenous administration. We calculated the SPIO signal through T2 value to evaluate KC phagocytic function. Intestinal permeability was assessed by measuring the permeability of 4kDa FITC-Dextran. We also measured LPS in the mice feces and LPS-binding protein mRNA level in the livers. Results: DKO mice accumulated fat in the liver when
fed a standard diet. Infiltration of inflammatory cells was observed only in the livers of DKO mice suggesting that DKO mice developed NASH. The steatosis and fibrosis in DKO livers
progressed with age. The T2 value in WT livers dramatically decreased after SPIO administration, whereas little signal reduction was seen in the livers of DKO mice. The KCs’ GSK-3 inhibitor function in the DKO mice decreased significantly compared with the WT mice. Furthermore, intestinal permeability, assessed by measuring plasma levels of 4kDa FITC-Dextran administered by an oral load, LPS in feces and LPS-binding protein mRNA level in the livers all increased significantly in the DKO mice. Conclusions: The DKO mouse is a novel animal model that develops mature-onset NASH. Impaired clearance of LPS due to KC dysfunction and increased selleck compound intestinal permeability appear to be important factors for the progression of NASH in DKO mice. Disclosures: The following people have nothing to disclose: Kentaro Akiyama, Eiji Warabi, Kosuke Okada, Miho Ikeuchi, Tetsuya Ueda, Katsumi Kose, Junichi Shoda Background: Granulocyte colony stimulating factor (G-CSF) administration had shown improvements in animal models of alcoholic steatohepatitis and fibrosis via anti-apoptotic effects. However, therapeutic effects of G-CSF on steatohepatitis have not been evaluated. We investigated the effects of G-CSF on NAFLD model. Methods: Four-week old male C57BL/6J (n=46) mice were divided into control, NAFLD, and three G-CSF groups (G1-G3). Control group was fed normal chow while NAFLD and G-CSF groups were fed high fat diet for 12 weeks.