Ggt7-KO Mouse

Ggt7, also known as GGTL3 or GGT4, is a member of the gamma-glutamyltransferase gene family. It has been implicated in multiple biological functions, including its role in glutathione metabolism and redox-sensitive processes [8]. It is also associated with pathways related to cell growth, mitophagy, and cholesterol metabolism [2,9]. The study of Ggt7 using genetic models can provide insights into its normal functions and its implications in disease.

In pancreatic cancer, knockdown of TXNDC12, which interacts with Ggt7, led to decreased intracellular GSH content, increased levels of pro-ferroptosis factors, and inhibited cell proliferation, migration, and invasion. Overexpression of Ggt7 reversed these effects, suggesting that Ggt7 is involved in inhibiting ferroptosis in pancreatic cancer cells [1].

In gastric cancer, Ggt7 was frequently downregulated by promoter methylation. High-expression of Ggt7 in adjacent non-tumor tissues was associated with favorable survival. Ggt7 inhibited gastric cancer cell growth, cell cycle progression, migration, and invasion. It induced mitophagy by directly binding with RAB7, inhibited intracellular ROS, and suppressed MAPK signaling [2].

In glioblastoma, GBM patients with low Ggt7 expression had a worse prognosis. Exogenous expression of Ggt7 reduced cell proliferation and anchorage-independent growth, while decreasing Ggt7 expression increased proliferation. Intracranial injection of cells with reduced Ggt7 expression increased tumor growth in mice. Enhanced Ggt7 expression reduced ROS levels, indicating its role in regulating anti-oxidative damage in glioblastoma [6].

In rats with collagen-induced arthritis, downregulation of colonic Ggt7 was observed, and specific bioactive polysaccharide intervention could upregulate Ggt7 expression, alleviating the arthritis [3].

Polymorphic loci of the Ggt7 gene were associated with an increased risk of acute pancreatitis when exposed to certain risk factors [5].

A genome-wide association study identified an association between genetic variants in Ggt7 and hypertension [4].

In a multi-omics study of ADHD, Ggt7 was among the genes with significant causal alternative splicing events [7].

In a study on cholesterol and lipid homeostasis, Ggt7, as a SREBP2-dependent target, positively regulated cellular cholesterol levels, interacted with MYH10 to control LDL-C uptake, and genetic ablation of Ggt7 in mice led to reduced serum cholesterol levels [9].

In port wine birthmark patient-derived induced pluripotent stem cells, upregulation of Ggt7 was found in association with upregulated glutathione metabolism [10].

In conclusion, Ggt7 plays crucial roles in multiple biological processes and disease conditions. Through model-based research, it has been shown to be involved in cancer development, arthritis alleviation, and the regulation of cholesterol metabolism, among others. The use of gene knockout or conditional knockout mouse models, as well as other genetic manipulation models, has been instrumental in revealing these functions, providing valuable insights into potential therapeutic targets for various diseases.

References:

1. Xu, Xiangrong, Hei, Yu, Wang, Bobo, Zhang, Jing, Wang, Fenghui. 2024. TXNDC12 inhibits pancreatic tumor cells ferroptosis by regulating GSH/GGT7 and promotes its growth and metastasis. In Journal of Cancer, 15, 3913-3929. doi:10.7150/jca.93208. https://pubmed.ncbi.nlm.nih.gov/38911386/

2. Wang, Xiaohong, Zhang, Lianhai, Chan, Francis K L, Yu, Jun, Liang, Jessie Qiaoyi. 2022. Gamma-glutamyltransferase 7 suppresses gastric cancer by cooperating with RAB7 to induce mitophagy. In Oncogene, 41, 3485-3497. doi:10.1038/s41388-022-02339-1. https://pubmed.ncbi.nlm.nih.gov/35662282/

3. Wang, Chunyan, Chen, Yunjing, Zhang, Guangwen, Peng, Xichun, Luo, Jianming. 2020. Recovery of Ggt7 and Ace Expressions in the Colon Alleviates Collagen-Induced Arthritis in Rats by Specific Bioactive Polysaccharide Intervention. In Journal of agricultural and food chemistry, 68, 14531-14539. doi:10.1021/acs.jafc.0c06252. https://pubmed.ncbi.nlm.nih.gov/33226212/

4. Tan, Chengcheng, Zhang, Hongfu, Yu, Dong, Wang, Qing, Xu, Chengqi. . A genome-wide association study identifies novel association between genetic variants in GGT7 and LINC00944 and hypertension. In Clinical and translational medicine, 11, e388. doi:10.1002/ctm2.388. https://pubmed.ncbi.nlm.nih.gov/34047475/

5. Samgina, T A, Lazarenko, V A. 2022. [The role of polymorphic variants rs11546155 and rs6119534 of the GGT7 gene and risk factors in the development of acute pancreatitis]. In Voprosy pitaniia, 91, 43-50. doi:10.33029/0042-8833-2022-91-2-43-50. https://pubmed.ncbi.nlm.nih.gov/35596634/

6. Bui, Timothy T, Nitta, Ryan T, Kahn, Suzana A, Recht, Lawrence, Li, Gordon. 2015. γ-Glutamyl transferase 7 is a novel regulator of glioblastoma growth. In BMC cancer, 15, 225. doi:10.1186/s12885-015-1232-y. https://pubmed.ncbi.nlm.nih.gov/25884624/

7. Wang, Jingkai, Zhu, Qiu-Wen, Mai, Jia-Hao, Liang, Jiatong, Zhou, Ji-Yuan. . A multi-omics study of brain tissue transcription and DNA methylation revealing the genetic pathogenesis of ADHD. In Briefings in bioinformatics, 25, . doi:10.1093/bib/bbae502. https://pubmed.ncbi.nlm.nih.gov/39406522/

8. Heisterkamp, Nora, Groffen, John, Warburton, David, Sneddon, Tam P. 2008. The human gamma-glutamyltransferase gene family. In Human genetics, 123, 321-32. doi:10.1007/s00439-008-0487-7. https://pubmed.ncbi.nlm.nih.gov/18357469/

9. Shan, Haihuan, Fan, Shuangshuang, Li, Quanrun, Yu, Kun, Fei, Teng. 2025. Systematic interrogation of functional genes underlying cholesterol and lipid homeostasis. In Genome biology, 26, 59. doi:10.1186/s13059-025-03531-8. https://pubmed.ncbi.nlm.nih.gov/40098013/

10. Nguyen, Vi, Kravitz, Jacob, Gao, Chao, Nelson, J Stuart, Tan, Wenbin. 2023. Perturbations of Glutathione and Sphingosine Metabolites in Port Wine Birthmark Patient-Derived Induced Pluripotent Stem Cells. In Metabolites, 13, . doi:10.3390/metabo13090983. https://pubmed.ncbi.nlm.nih.gov/37755263/