Nonalcoholic steatohepatitis (NASH) has the potential to progress to fibrosis, cirrhosis, and hepatocellular carcinoma. Upregulation of sonic hedgehog (Shh) has been documented in development of NASH through sustained cell stress. At the same time, transforming growth factor-β1 (TGF-β1), which is a central element in fibrogenic reactions in various diseases and sites, has been reported to be associated with hepatic inflammation and fibrotic reaction. To explore crosstalk between Shh and TGF-β1 in the development and progression of NASH, we investigated the expression of both these proteins in 135 human specimens of NASH, 35 fatty liver specimens, 35 specimens of alcoholic steatohepatitis with immunohistochemistry. Shh protein was expressed in the cytoplasm of ballooned hepatocytes with an ubiquitin-like pattern. In addition, a few scattered apoptotic hepatocytes in the inflammatory foci showed homogeneous cytoplasmic Shh expression. TGF-β1 protein was observed mainly in the activated hepatic stellate cells (HSCs) which were located in the inflammatory foci surrounding ballooned hepatocytes. Moreover, the mRNA levels of both Shh and TGF-β1 in the liver biopsy specimens from NASH patients was significantly increased compared with those in fatty liver patients. Statistically, there was a significant association of the expressions of Shh and TGF-β1 proteins in NASH (r=0.6, P<0.05). In addition, increased expression of Shh protein significantly parallels the severity of hepatocellular ballooning, lobular, and portal inflammatory responses and progression of fibrosis in NASH patients. Moreover, we found that much HSCs transformed into myofibroblast-like phenotype and migrated downward to HepG2 hepatocellular carcinoma cells with overexpression of Shh by transwell assay. We also observed overexpression of proteins of Shh and TGF-β1 in cultured activated HSCs with confocal microscopy. These findings strongly suggest there is interplay between Shh and TGF-β1 in hepatic inflammatory reactions. Shh secreted through damaged hepatocytes may result in activation of TGF-β1 and subsequent transformation of HSCs, which together modulate the progression of human NASH.

中文翻译：

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Sonic Hedgehog 与转化生长因子-β1 在人类非酒精性脂肪性肝炎中的新相互作用

非酒精性脂肪性肝炎 (NASH) 有可能发展为纤维化、肝硬化和肝细胞癌。已经记录了通过持续的细胞应激在 NASH 发展中声波刺猬 (Shh) 的上调。同时，据报道，转化生长因子-β1 (TGF-β1) 是各种疾病和部位纤维化反应的核心要素，据报道与肝脏炎症和纤维化反应有关。为了探索 Shh 和 TGF-β1 在 NASH 发展和进展中的串扰，我们用免疫组织化学研究了这两种蛋白质在 135 份 NASH 人类标本、35 份脂肪肝标本、35 份酒精性脂肪性肝炎标本中的表达。Shh 蛋白以泛素样模式在膨胀的肝细胞的细胞质中表达。此外，炎症病灶中少数散在的凋亡肝细胞显示均匀的细胞质Shh表达。TGF-β1 蛋白主要在活化的肝星状细胞 (HSC) 中观察到，这些细胞位于膨胀的肝细胞周围的炎症灶中。此外，与脂肪肝患者相比，NASH 患者肝活检标本中 Shh 和 TGF-β1 的 mRNA 水平显着增加。从统计上看，NASH中Shh和TGF-β1蛋白的表达存在显着相关性（r=0.6，P<0.05）。此外，在 NASH 患者中，Shh 蛋白表达的增加与肝细胞气球样变、小叶和门静脉炎症反应的严重程度以及纤维化的进展显着平行。而且，我们发现许多 HSC 转化为肌成纤维细胞样表型并向下迁移到 HepG2 肝细胞癌细胞，并通过 Transwell 测定法过度表达 Shh。我们还用共聚焦显微镜观察到培养的活化 HSC 中 Shh 和 TGF-β1 蛋白的过表达。这些发现强烈表明在肝脏炎症反应中 Shh 和 TGF-β1 之间存在相互作用。通过受损肝细胞分泌的 Shh 可能导致 TGF-β1 的激活和随后的 HSC 转化，这些共同调节人类 NASH 的进展。这些发现强烈表明在肝脏炎症反应中 Shh 和 TGF-β1 之间存在相互作用。通过受损肝细胞分泌的 Shh 可能导致 TGF-β1 的激活和随后的 HSC 转化，这些共同调节人类 NASH 的进展。这些发现强烈表明在肝脏炎症反应中 Shh 和 TGF-β1 之间存在相互作用。通过受损肝细胞分泌的 Shh 可能导致 TGF-β1 的激活和随后的 HSC 转化，这些共同调节人类 NASH 的进展。