角蛋白23（Krt23/K23）为近年新发现的一种酸性角蛋白，在慢性肝炎伴发胆管反应和肝细胞再生时K23表达显著上调。令人感兴趣的是肝硬化患者血清中可检测到K23。作为一种潜在肝硬化无创诊断标志物，目前Krt23与肝纤维化程度相关性以及调控机制尚不清楚。我们的前期工作发现肝内K23表达水平与肝硬化患者不同纤维化病理分期相关；基础实验提示Myc是K23上游基因；PPARα激动剂可上调K23。据此我们推测K23可促进肝纤维化进展，PPARα/Myc轴可调控K23的表达进而参与了肝纤维化。本课题拟首先扩大样本进一步验证血清及肝内K23表达水平与肝硬化患者纤维化程度相关；利用PPARα和Myc细胞特异敲除小鼠，胆管结扎以及DDC喂养建立肝纤维化模型，经体内外实验阐明K23可促进肝纤维化，PPARα/Myc轴调控K23表达的分子机制。本课题的实施将为Krt23作为临床肝纤维化无创诊断标志奠定理论基础

Keratin23(Krt23), as a type I acidic cytokeratin, which expresses on cholangiocytes and hepatocytes in liver. It will be up-regulated as well as ductular reaction and hepatocyte proliferation during chronic hepatitis and liver fibrosis. Especially interesting, Krt23 may be a potential non-invasive diagnostic marker of cirrhosis since it can be detected in the serum of patients with cirrhosis. But the role and modulation of Krt23 in the mechanism of liver fibrogenesis is unknown so far. Our previous work showed the expression level of Krt23 in liver is correlated with the degree of liver fibrosis in the patients with chronic hepatitis B and cirrhosis due to HBV infection. Further basic research results indicated c-Myc is the upstream of Krt23，Wy14643 treatment up regulates the expression of Krt23. Based on our previous work we have a hypothesis that PPARalpha/c-Myc signaling modulates Krt23 to promote liver fibrogenesis. Next, we will confirm Krt23 level in serum and liver tissue have a good correlation with the degree of fibrosis using the larger samples and then we will use Krt23-/-, Myc-/-, PPARA-/- hepatocyte-specific knockout mice and primary hepatocyte to study the role and mechanism of Krt23 regulated by PPARalpha/c-Myc signaling in vivo and in vitro. By this research, we will clarify Krt23 can be a useful promising non-invasive diagnostic marker/warning biomarker of early stage of cirrhosis and PPARalpha/c-Myc signaling via modulating Keratin 23 promotes liver fibrogenesis.