Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str 10, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, University of Tübingen, Otfried-Müller-Str 10, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
Interfakultäres Institut für Biochemie, University of Tübingen, Hoppe-Seyler-Str. 4, 72076 Tübingen, Germany.
Metabolism. 2018 Nov;88:22-30. doi: 10.1016/j.metabol.2018.09.001. Epub 2018 Sep 6.
The activation of hepatic stellate cells (HSCs) plays a crucial role in liver fibrosis, however the role of HSCs is less understood in hepatic insulin resistance. Since in the liver cGMP-dependent protein kinase I (cGKI) was detected in HSC but not in hepatocytes, and cGKI-deficient mice that express cGKI selectively in smooth muscle but not in other cell types (cGKI-SM mice) displayed hepatic insulin resistance, we hypothesized that cGKI modulates HSC activation and insulin sensitivity.
To study stellate cell activation in cGKI-SM mice, retinol storage and gene expression were studied. Moreover, in the human stellate cell line LX2, the consequences of cGKI-silencing on gene expression were investigated. Finally, cGKI expression was examined in human liver biopsies covering a wide range of liver fat content.
Retinyl-ester concentrations in the liver of cGKI-SM mice were lower compared to wild-type animals, which was associated with disturbed expression of genes involved in retinol metabolism and inflammation. cGKI-silenced LX2 cells showed an mRNA expression profile of stellate cell activation, altered matrix degradation and activated chemokine expression. On the other hand, activation of LX2 cells suppressed cGKI expression. In accordance with this finding, in human liver biopsies, we observed a negative correlation between cGKI mRNA and liver fat content.
These results suggest that the lack of cGKI possibly leads to stellate cell activation, which stimulates chemokine expression and activates inflammatory processes, which could disturb hepatic insulin sensitivity.
肝星状细胞（HSCs）的激活在肝纤维化中起着关键作用，但在肝胰岛素抵抗中，HSCs 的作用知之甚少。由于在 HSC 中检测到 cGMP 依赖性蛋白激酶 I（cGKI），而在肝细胞中未检测到，并且在不表达 cGKI 的其他细胞类型中选择性表达 cGKI 的平滑肌中表达 cGKI 的缺乏小鼠（cGKI-SM 小鼠）显示出肝胰岛素抵抗，我们假设 cGKI 调节 HSC 激活和胰岛素敏感性。
为了研究 cGKI-SM 小鼠中星状细胞的激活，研究了视黄醇储存和基因表达。此外，在人星状细胞系 LX2 中，研究了 cGKI 沉默对基因表达的影响。最后，检查了涵盖广泛肝脂肪含量范围的人肝活检中 cGKI 的表达。
cGKI-SM 小鼠肝脏中的视黄醇酯浓度低于野生型动物，这与涉及视黄醇代谢和炎症的基因表达紊乱有关。沉默 cGKI 的 LX2 细胞显示出星状细胞激活、基质降解改变和趋化因子表达激活的 mRNA 表达谱。另一方面，LX2 细胞的激活抑制了 cGKI 的表达。与此发现一致，在人类肝活检中，我们观察到 cGKI mRNA 与肝脂肪含量之间存在负相关。
这些结果表明，cGKI 的缺乏可能导致星状细胞激活，从而刺激趋化因子表达并激活炎症过程，从而干扰肝胰岛素敏感性。
