Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago and Research and Development Division, Jesse Brown VA Medical Center, Chicago, Illinois, USA.
Department of Pathology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois, USA.
J Endocrinol. 2021 Jan;248(1):31-44. doi: 10.1530/JOE-20-0326.
A reduction in hepatocyte growth hormone (GH)-signaling promotes non-alcoholic fatty liver disease (NAFLD). However, debate remains as to the relative contribution of the direct effects of GH on hepatocyte function vs indirect effects, via alterations in insulin-like growth factor 1 (IGF1). To isolate the role of hepatocyte GH receptor (GHR) signaling, independent of changes in IGF1, mice with adult-onset, hepatocyte-specific GHR knockdown (aHepGHRkd) were treated with a vector expressing rat IGF1 targeted specifically to hepatocytes. Compared to GHR-intact mice, aHepGHRkd reduced circulating IGF1 and elevated GH. In male aHepGHRkd, the shift in IGF1/GH did not alter plasma glucose or non-esterified fatty acids (NEFA), but was associated with increased insulin, enhanced systemic lipid oxidation and reduced white adipose tissue (WAT) mass. Livers of male aHepGHRkd exhibited steatosis associated with increased de novo lipogenesis, hepatocyte ballooning and inflammation. In female aHepGHRkd, hepatic GHR protein levels were not detectable, but moderate levels of IGF1 were maintained, with minimal alterations in systemic metabolism and no evidence of steatosis. Reconstitution of hepatocyte IGF1 in male aHepGHRkd lowered GH and normalized insulin, whole body lipid utilization and WAT mass. However, IGF1 reconstitution did not reduce steatosis or eliminate liver injury. RNAseq analysis showed IGF1 reconstitution did not impact aHepGHRkd-induced changes in liver gene expression, despite changes in systemic metabolism. These results demonstrate the impact of aHepGHRkd is sexually dimorphic and the steatosis and liver injury observed in male aHepGHRkd mice is autonomous of IGF1, suggesting GH acts directly on the adult hepatocyte to control NAFLD progression.
肝细胞生长激素 (GH) 信号的减少会促进非酒精性脂肪性肝病 (NAFLD)。然而，关于 GH 对肝细胞功能的直接作用与通过改变胰岛素样生长因子 1 (IGF1) 的间接作用的相对贡献仍存在争议。为了分离独立于 IGF1 变化的肝细胞 GH 受体 (GHR) 信号的作用，使用专门针对肝细胞表达大鼠 IGF1 的载体对具有成年期肝细胞特异性 GHR 敲低 (aHepGHRkd) 的小鼠进行了处理。与 GHR 完整的小鼠相比，aHepGHRkd 降低了循环 IGF1 和升高了 GH。在雄性 aHepGHRkd 中，IGF1/GH 的转变并未改变血浆葡萄糖或非酯化脂肪酸 (NEFA)，但与胰岛素增加、全身脂质氧化增强和白色脂肪组织 (WAT) 质量减少有关。雄性 aHepGHRkd 的肝脏表现出与从头脂肪生成增加、肝细胞气球样变和炎症相关的脂肪变性。在雌性 aHepGHRkd 中，肝 GHR 蛋白水平无法检测到，但维持了中等水平的 IGF1，全身代谢变化极小，没有脂肪变性的证据。在雄性 aHepGHRkd 中重建肝细胞 IGF1 降低了 GH 并使胰岛素、全身脂质利用和 WAT 质量正常化。然而，IGF1 的重建并不能减少脂肪变性或消除肝损伤。RNAseq 分析表明，尽管系统代谢发生了变化，但 IGF1 的重建并没有影响 aHepGHRkd 诱导的肝脏基因表达变化。这些结果表明，aHepGHRkd 的影响具有性别二态性，并且在雄性 aHepGHRkd 小鼠中观察到的脂肪变性和肝损伤与 IGF1 无关，这表明 GH 直接作用于成年肝细胞来控制 NAFLD 的进展。
