Stepwise increase of total positive-area was observed according to the ballooning hepatocyte score. Total positive-area was significantly greater in the liver tissues from the patients with nonalcoholic steatohepatitis (n=47) than those from the patients with nonalcoholic fatty liver (n=7). We next examined the role of S100A8
in a NAFLD mice model. LD-fed mice, but not ND-fed mice, displayed hepatitis with steatosis, lobular inflammation, ballooning and fibrosis. S100A8-positive cells were observed in a part of hepatic leukocytes, and significantly greater in number in the livers of LD-fed mice compared with ND-fed mice. Flow cytometric analyses revealed that more than 80% of S100A8 positive cells were CD11b+ Gr-1high myeloid lineage cells and significantly increased in the livers of LD-fed Erismodegib molecular weight mice compared with ND-fed mice. S100A8 positive cells also expressed CXCR2, a chemokine receptor. We studied chemokine gene expressions in the livers of LD- and ND-fed Gefitinib cost mice. The gene expressions of Cxcl1, Cxcl2, and Mcp1 significantly elevated in the livers of LD-fed mice compared with ND-fed mice. In vitro study, palmitic acid upregulated the gene expressions
of Cxcl1 and Mcp1 in CL2, murine hepatocyte cell line. Hepatic leukocytes from LD-fed mice, but not those from ND-fed mice, spontaneously produced substantial amounts of CXCL1 as well as TNF-α. Moreover, S100A8 significantly induced production of CXCL1 as well as TNF-α from normal hepatic leukocytes. Conclusion: The present study suggested that upregulated Cxcl1 expressions in the livers of LD-fed mice led to the accumulation
of S100A8 positive cells via CXCR2 and that S100A8 produced TNF-α and Cxcl1. Taken together with human results, the amplification of S100A8-CXCL1 loop via CXCR2 might be involved in the development of NAFLD. Disclosures: Tetsuo Takehara – Grant/Research Support: Chugai Pharmaceutical Co., MSD K.K. The following people have nothing to disclose: Kaori Mukai, Takuya Miyagi, Yoshinobu Yokoyama, Teppei Dynein Yoshioka, Kumiko Nishio, Akira Nishio, Yoshiki Onishi, Satoshi Aono, Yoshinobu Saito, Satoshi Tanaka, Hayato Hikita, Ryotaro Sakamori, Naoki Hiramatsu, Harumasa Yoshihara, Yasuharu Imai, Tomohide Tatsumi Background and Aim: Free fatty acids play a critical role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatosis and steatohepatitis. Recent research has shown that apoptosis is a characteristic feature of hepatocytes in NAFLD. Meanwhile, a complex relationship is reported between apoptosis and autophagy in several disease models but not well established in NAFLD. In this study, we investigated the interplay between apoptosis and autophagy in NAFLD. Methods: HepG2 cells were cultured with saturated palmitic acid (PA). For in vivo studies, male C57BL/6J mice or Mx1-Cre mediated Atg7 knockout mice (Mx1-Cre Atg7 fl/fl), were fed high fat diet (HFD).