Department of Microbiology and Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, Beijing 100191, China.
Department of Anatomy and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Biomolecules. 2021 Feb 2;11(2):205. doi: 10.3390/biom11020205.
Golgi protein 73 (GP73) is upregulated in a variety of liver diseases, yet the detailed mechanism is poorly characterized. We analyzed GP73 in a retrospective cohort including 4211 patients with chronic liver disease (CLD) or hepatocellular carcinoma (HCC). The effect of deoxycholic acid (DCA) and nuclear factor-kappa B (NF-κB) on expression and release of GP73 in Huh-7 and SMMC7721 cells were studied. A mouse study was used to confirm our findings in vivo. A positive correlation was found between serum GP73 and total bile acid (TBA) in cirrhotic patients ( = 0.540, < 0.001), higher than that in non-cirrhotic CLD ( = 0.318, < 0.001) and HCC ( = 0.353, < 0.001) patients. In Huh-7 and SMMC7721 cells, DCA upregulated the expression and release of GP73 in a dose- and time-dependent manner. After overexpressing NF-κB p65, the promoter activity, GP73 messenger RNA (mRNA) level, and supernatant GP73 level were increased. The promotion effect of DCA on GP73 release was attenuated after inhibiting the NF-κB pathway. Mutating the binding sites of NF-κB in the sequence of the GP73 promoter led to a declined promoting effect of DCA on GP73. The upregulation role of DCA in GP73 expression through the NF-κB pathway was confirmed in vivo. In addition, exposure to DCA caused disassembly of Golgi apparatus. In summary, DCA upregulates the expression and release of GP73 via activating the NF-κB pathway and destroying the Golgi structure.
高尔基体蛋白 73（GP73）在多种肝脏疾病中上调，但详细机制尚不清楚。我们分析了包括 4211 例慢性肝病（CLD）或肝细胞癌（HCC）患者在内的回顾性队列中的 GP73。研究了脱氧胆酸（DCA）和核因子-κB（NF-κB）对 Huh-7 和 SMMC7721 细胞中 GP73 的表达和释放的影响。使用小鼠研究在体内证实了我们的发现。在肝硬化患者中，血清 GP73 与总胆汁酸（TBA）之间存在正相关（ = 0.540， < 0.001），高于非肝硬化 CLD（ = 0.318， < 0.001）和 HCC（ = 0.353， < 0.001）患者。在 Huh-7 和 SMMC7721 细胞中，DCA 以剂量和时间依赖的方式上调 GP73 的表达和释放。过表达 NF-κB p65 后，启动子活性、GP73 信使 RNA（mRNA）水平和上清液 GP73 水平增加。抑制 NF-κB 通路后，DCA 对 GP73 释放的促进作用减弱。突变 GP73 启动子序列中 NF-κB 的结合位点导致 DCA 对 GP73 的促进作用下降。DCA 通过 NF-κB 通路上调 GP73 表达的作用在体内得到了证实。此外，DCA 暴露导致高尔基体解体。总之，DCA 通过激活 NF-κB 通路和破坏高尔基体结构上调 GP73 的表达和释放。
