Molecular mechanism for prevention of high-fat and -cholesterol-induced fibrotic steatohepatitis and development of the non-invasive biomarker

高脂高脂饮食(HFC)诱导的肝纤维化程度SHRSP5/Dmcr大于SHRSP。这是由于前者对UGT、CAR和PXR的抑制作用大于后者。男性的纤维化面积大于女性。HFC饮食对雌性大鼠UGT活性和Car、PXR的表达无明显抑制作用，而对雄性大鼠UGT活性和Car、PXR表达明显抑制，提示该酶及其分泌胆汁酸的核受体可能是导致组织病理学发现性别差异的重要原因之一。EPA通过抑制p65/p50的升高来预防炎症，但不影响纤维化的发展。HFC饮食主要通过降低caspase3/7的活性导致肝脏坏死。血清K18Asp396水平与肝细胞坏死和纤维化呈正相关，提示K18Asp396水平可能是肝细胞坏死和纤维化的一个良好的无创性生物标志物。饲喂HFC后，胆酸/鹅去氧胆酸(CDCA)比值显著降低。

High-fat and-cholesterol diet (HFC) induced hepatic fibrosis greater in SHRSP5/Dmcr than SHRSP. This was due to greater suppression of UGT, CAR and PXR in the former than the latter. The fibrosis area was greater in males than females. The UGT activity and expressions of CAR and PXR, were not suppressed by HFC diet in females, while significantly suppressed in males, suggesting this enzyme and its nuclea receptors excreting bile acid may be one of important role in the sex differences in the histopathological finding. EPA prevented inflammation by inhibiting increase of p65/p50, however, did not influence fibrosis development.HFC diet mainly induced necrosis in the liver by decrease in caspase 3/7 activity. Serum K18Asp396 levels were positively correlated with hepatocyte necrosis and fibrosis, suggesting that the levels may be a good noninvasive biomarker of these findingss. According to HFC-diet feeding, ratio of cholic acid/chenodeoxycholic acid (CDCA)significantly decreased.