Liver Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Hepatology. 2010 Mar;51(3):974-85. doi: 10.1002/hep.23421.
There are no effective antifibrotic therapies for patients with liver diseases. We performed an experimental and translational study to investigate whether ghrelin, an orexigenic hormone with pleiotropic properties, modulates liver fibrogenesis. Recombinant ghrelin was administered to rats with chronic (bile duct ligation) and acute (carbon tetrachloride) liver injury. Hepatic gene expression was analyzed by way of microarray analysis and quantitative polymerase chain reaction. The hepatic response to chronic injury was also evaluated in wild-type and ghrelin-deficient mice. Primary human hepatic stellate cells were used to study the effects of ghrelin in vitro. Ghrelin hepatic gene expression and serum levels were assessed in patients with chronic liver diseases. Ghrelin gene polymorphisms were analyzed in patients with chronic hepatitis C. Recombinant ghrelin treatment reduced the fibrogenic response, decreased liver injury and myofibroblast accumulation, and attenuated the altered gene expression profile in bile duct-ligated rats. Moreover, ghrelin reduced the fibrogenic properties of hepatic stellate cells. Ghrelin also protected rats from acute liver injury and reduced the extent of oxidative stress and inflammation. Ghrelin-deficient mice developed exacerbated hepatic fibrosis and liver damage after chronic injury. In patients with chronic liver diseases, ghrelin serum levels decreased in those with advanced fibrosis, and ghrelin gene hepatic expression correlated with expression of fibrogenic genes. In patients with chronic hepatitis C, polymorphisms of the ghrelin gene (-994CT and -604GA) influenced the progression of liver fibrosis.
Ghrelin exerts antifibrotic effects in the liver and may represent a novel antifibrotic therapy.
对于患有肝脏疾病的患者，目前尚无有效的抗纤维化疗法。我们进行了一项实验和转化研究，以研究促胃液素（一种具有多种特性的食欲激素）是否调节肝纤维化。给患有慢性（胆管结扎）和急性（四氯化碳）肝损伤的大鼠施用重组促胃液素。通过微阵列分析和定量聚合酶链反应分析肝基因表达。还在野生型和促胃液素缺乏型小鼠中评估了对慢性损伤的肝反应。使用原代人肝星状细胞研究促胃液素的体外作用。评估了慢性肝脏疾病患者的促胃液素肝基因表达和血清水平。分析了慢性丙型肝炎患者的促胃液素基因多态性。重组促胃液素治疗可降低纤维生成反应，减少肝损伤和肌成纤维细胞积聚，并减轻胆管结扎大鼠改变的基因表达谱。此外，促胃液素可降低肝星状细胞的纤维生成特性。促胃液素还可保护大鼠免受急性肝损伤，并减少氧化应激和炎症的程度。慢性损伤后，促胃液素缺乏型小鼠发生更严重的肝纤维化和肝损伤。在慢性肝脏疾病患者中，纤维化程度较重的患者促胃液素血清水平降低，肝基因表达与纤维生成基因的表达相关。在慢性丙型肝炎患者中，促胃液素基因（-994CT 和-604GA）的多态性影响肝纤维化的进展。
促胃液素在肝脏中具有抗纤维化作用，可能代表一种新的抗纤维化疗法。
