GH directly inhibits steatosis and liver injury in a sex-dependent and IGF1-independent manner.
GH directly inhibits steatosis and liver injury in a sex-dependent and IGF1-independent manner.
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DOI：
10.1530/joe-20-0326
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发表时间：
2021-01
期刊：
影响因子：
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通讯作者：
Kineman RD
中科院分区：
文献类型：
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作者：
Sarmento-Cabral A;Del Rio-Moreno M;Vazquez-Borrego MC;Mahmood M;Gutierrez-Casado E;Pelke N;Guzman G;Subbaiah PV;Cordoba-Chacon J;Yakar S;Kineman RD
肝细胞生长激素（GH）信号的减少会促进非酒精性脂肪肝（NAFLD）。然而，关于 GH 对肝细胞功能的直接影响与通过改变胰岛素样生长因子 1 (IGF1) 的间接影响之间的相对贡献仍然存在争议。为了分离肝细胞 GH 受体 (GHR) 信号传导的作用（独立于 IGF1 的变化），用表达特异性针对肝细胞的大鼠 IGF1 的载体治疗成年发病的肝细胞特异性 GHR 敲低 (aHepGHRkd) 的小鼠。与 GHR 完整小鼠相比，aHepGHRkd 减少了循环 IGF1 并升高了 GH。在男性 aHepGHRkd 中，IGF1/GH 的变化不会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。男性 aHepGHRkd 的肝脏表现出与从头脂肪生成增加、肝细胞膨胀和炎症相关的脂肪变性。在女性 aHepGHRkd 中，检测不到肝脏 GHR 蛋白水平，但 IGF1 保持中等水平，全身代谢变化最小，没有脂肪变性的证据。男性 aHepGHRkd 中肝细胞 IGF1 的重建降低了 GH 并使胰岛素、全身脂质利用率和 WAT 质量正常化。然而，IGF1 重建并不能减少脂肪变性或消除肝损伤。 RNAseq 分析显示，尽管全身代谢发生了变化，IGF1 重建并不影响 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，表明 GH 直接作用于成年肝细胞以控制 NAFLD 进展。
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 versus 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.