Hoppe Andreas, Ilkavets Iryna, Dooley Steven, Holzhütter Hermann-Georg
Institute for Biochemistry, Charité University Medicine Berlin, Charitéplatz 1/Virchowweg 6, 10117 Berlin, Germany.
Molecular Hepatology and Alcohol Associated Diseases, Medical Clinic II, Medical Faculty Mannheim at Heidelberg University, Theodor-Kutzer-Ufer 1-3, H42 E4, 68167 Mannheim, Germany.
Metabolites. 2012 Nov 21;2(4):983-1003. doi: 10.3390/metabo2040983.
TGFb signaling plays a major role in the reorganization of liver tissue upon injury and is an important driver of chronic liver disease. This is achieved by a deep impact on a cohort of cellular functions. To comprehensively assess the full range of affected metabolic functions, transcript changes of cultured mouse hepatocytes were analyzed with a novel method (ModeScore), which predicts the activity of metabolic functions by scoring transcript expression changes with 987 reference flux distributions, which yielded the following hypotheses. TGFb multiplies down-regulation of most metabolic functions occurring in culture stressed controls. This is especially pronounced for tyrosine degradation, urea synthesis, glucuronization capacity, and cholesterol synthesis. Ethanol degradation and creatine synthesis are down-regulated only in TGFb treated hepatocytes, but not in the control. Among the few TGFb dependently up-regulated functions, synthesis of various collagens is most pronounced. Further interesting findings include: down-regulation of glucose export is postponed by TGFb, TGFb up-regulates the synthesis capacity of ketone bodies only as an early response, TGFb suppresses the strong up-regulation of Vanin, and TGFb induces re-formation of ceramides and sphingomyelin.
转化生长因子β（TGFβ）信号通路在肝脏损伤后的组织重塑中起主要作用，是慢性肝病的重要驱动因素。这是通过对一系列细胞功能产生深刻影响来实现的。为了全面评估受影响的代谢功能的全范围，采用一种新方法（模式评分法）分析培养的小鼠肝细胞的转录本变化，该方法通过用987种参考通量分布对转录本表达变化进行评分来预测代谢功能的活性，得出了以下假设。TGFβ使培养的应激对照中发生的大多数代谢功能的下调成倍增加。这在酪氨酸降解、尿素合成、葡萄糖醛酸化能力和胆固醇合成方面尤为明显。乙醇降解和肌酸合成仅在TGFβ处理的肝细胞中下调，而在对照中未下调。在少数依赖TGFβ上调的功能中，各种胶原蛋白的合成最为明显。进一步有趣的发现包括：TGFβ延迟葡萄糖输出的下调，TGFβ仅作为早期反应上调酮体的合成能力，TGFβ抑制Vanin的强烈上调，以及TGFβ诱导神经酰胺和鞘磷脂的重新形成。
