Ghrelin treatment effects on hepatic gene expression in rats submitted to Bile Duct Ligation

Hepatic fibrosis, the wound-healing response to repeated liver injury, ultimately leads to cirrhosis. There is an urgent need to develop effective antifibrotic therapies. Ghrelin (encoded by Ghrl) is an orexigenic hormone that has pleiotrophic functions including protection against cell death1. Here we investigate whether ghrelin modulates liver fibrosis and protects from acute liver injury. Recombinant ghrelin reduced the fibrogenic response to prolonged bile duct ligation in rats. This effect was associated with decreased liver injury and myofibroblast accumulation as well as attenuation of the altered gene expression profile. Ghrelin also reduced fibrogenic properties in cultured hepatic stellate cells. Moreover, Ghrl-/- mice developed exacerbated hepatic fibrosis and liver damage after chronic injury. Ghrelin also protected rat livers from acute liver injury and reduced the extent of oxidative stress and the inflammatory response. In patients with chronic liver diseases, ghrelin serum levels decreased in those with advanced fibrosis and hepatic expression of the ghrelin gene correlated with expression of fibrogenic genes. Finally, in patients with chronic hepatitis C, single nucleotide polymorphisms of the ghrelin gene (-994CT and –604GA) influenced the progression of liver fibrosis. We conclude that ghrelin exerts antifibrotic effects on the liver and may represent a novel antifibrotic therapy.肝纤维化（Hepatic fibrosis）是机体针对反复肝损伤产生的伤口愈合反应，最终可进展为肝硬化。目前亟需开发有效的抗纤维化治疗手段。 饥饿素（Ghrelin，由Ghrl基因编码）是一种促食欲激素，具备多种生物学功能，包括抑制细胞死亡¹。本研究旨在探究饥饿素是否可调节肝纤维化进程并抵御急性肝损伤。 重组饥饿素可降低大鼠长期胆管结扎后的纤维化反应。该效应与肝损伤减轻、肌成纤维细胞（myofibroblast）聚集减少以及异常基因表达谱的缓解密切相关。饥饿素还可抑制培养状态下肝星状细胞（hepatic stellate cells）的纤维化相关特性。 此外，Ghrl基因敲除（Ghrl-/-）小鼠在遭受慢性损伤后，肝纤维化程度与肝损伤均会加剧。饥饿素同样可保护大鼠肝脏免受急性肝损伤，并减轻氧化应激与炎症反应的程度。 在慢性肝病患者中，伴进展期肝纤维化者的血清饥饿素水平下降，且肝脏内饥饿素基因的表达与纤维化相关基因的表达存在相关性。最后，在慢性丙型肝炎（chronic hepatitis C）患者中，饥饿素基因的单核苷酸多态性（single nucleotide polymorphisms）位点（-994C>T与-604G>A）会影响肝纤维化的进展。 综上，饥饿素对肝脏具有抗纤维化作用，有望成为新型抗纤维化治疗方案。