Han Mei, Nwosu Zeribe Chike, Piorońska Weronika, Ebert Matthias Philip, Dooley Steven, Meyer Christoph
Section Molecular Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Department of Internal Medicine, The Second Hospital of Dalian Medical University, Dalian, China.
Front Physiol. 2020 Jan 31;10:1606. doi: 10.3389/fphys.2019.01606. eCollection 2019.
Caveolin-1 (CAV1) is a membrane protein associated with metabolism in various cell types. The transforming growth factor beta (TGF-β) is a pro-fibrogenic cytokine in the liver, but its metabolic gene signatures remain unclear to date. We have previously shown that CAV1 alters TGF-β signaling and blocks its pro-apoptotic function. Here, we defined TGF-β-induced metabolic gene signatures in hepatocytes and assessed whether CAV1 abundance affects TGF-β control of those metabolic genes. Microarray analyses of primary hepatocytes after TGF-β stimulation (48 h) showed differential expression of 4224 genes, of which 721 are metabolic genes (adjusted < 0.001). Functional annotation analysis revealed that TGF-β mainly suppresses metabolic gene network, including genes involved in glutathione, cholesterol, fatty acid, and amino acid metabolism. TGF-β also upregulated several genes related to glycan metabolism and ion transport. In contrast to TGF-β effects, CAV1 knockdown triggered the upregulation of metabolic genes. Immortalized mouse hepatocytes (AML12 cells) were used to validate the gene changes induced by TGF-β stimulation and CAV1 knockdown. Noteworthy, of the TGF-β metabolic target genes, CAV1 modulated the expression of 228 (27%). In conclusion, we present several novel metabolic gene signatures of TGF-β in hepatocytes and show that CAV1 abundance alters almost a third of these genes. These findings could enable a better understanding of TGF-β function in normal and diseased liver especially where differential CAV1 level is implicated.
小窝蛋白-1（CAV1）是一种与多种细胞类型代谢相关的膜蛋白。转化生长因子β（TGF-β）是肝脏中的一种促纤维化细胞因子，但其代谢基因特征至今仍不清楚。我们之前已经表明，CAV1会改变TGF-β信号传导并阻断其促凋亡功能。在此，我们确定了TGF-β在肝细胞中诱导的代谢基因特征，并评估了CAV1丰度是否会影响TGF-β对这些代谢基因的调控。对TGF-β刺激（48小时）后的原代肝细胞进行微阵列分析，结果显示4224个基因表达存在差异，其中721个是代谢基因（校正后<0.001）。功能注释分析表明，TGF-β主要抑制代谢基因网络，包括参与谷胱甘肽、胆固醇、脂肪酸和氨基酸代谢的基因。TGF-β还上调了一些与聚糖代谢和离子转运相关的基因。与TGF-β的作用相反，CAV1基因敲低引发了代谢基因的上调。永生化小鼠肝细胞（AML12细胞）被用于验证TGF-β刺激和CAV1基因敲低所诱导的基因变化。值得注意的是，在TGF-β的代谢靶基因中，CAV1调节了228个基因的表达（27%）。总之，我们展示了TGF-β在肝细胞中的几个新的代谢基因特征，并表明CAV1丰度改变了几乎三分之一的这些基因。这些发现有助于更好地理解TGF-β在正常和患病肝脏中的功能尤其是在涉及CAV1水平差异的情况下。
