Tm6sf2, or Transmembrane 6 superfamily member 2, is located on chromosome 19 (19p12) and has emerged as a key regulator in lipid metabolism [1,2]. It is involved in pathways such as intestinal cholesterol absorption, hepatic cholesterol biosynthesis and transport, and very-low-density lipoprotein (VLDL) lipidation [1,5,7]. Genetic studies have associated Tm6sf2 variants with plasma lipid traits, cardiovascular disease (CVD), and non-alcoholic fatty liver disease (NAFLD), highlighting its biological importance [1,2,8]. Mouse models with overexpression or knockdown/knockout of Tm6sf2 have been crucial for in vivo validation of its role in regulating plasma lipid levels [1].

In mouse models, hepatocyte-specific Tm6sf2 knockout (Tm6sf2 ∆hep) exacerbated tumour formation in metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma (MASLD-HCC), while overexpression had opposite effects, suggesting Tm6sf2 can promote antitumour immunity via inhibiting the NF-κB signalling pathway to activate cytotoxic CD8+ T cells [3]. Myeloid cell-specific Tm6sf2 knockout (LysM Cre+/Tm6sf2fl/fl/ApoE-/-, TM6 mKO) inhibited atherosclerosis and decreased foam cells in plaques without changing plasma lipid profiles, as RNA sequencing showed downregulation of genes related to inflammation, cholesterol uptake, and endoplasmic reticulum stress in bone marrow-derived macrophages [4]. Tm6sf2 -/- rats had higher hepatic triglyceride content and lower plasma cholesterol levels, with reduced rates of dietary and hepatic triglyceride appearance in blood, and decreased lipid content in newly secreted VLDLs, indicating Tm6sf2 acts in the smooth endoplasmic reticulum to promote VLDL lipidation [5]. Tm6sf2 intestinal epithelial cell-specific knockout (Tm6sf2ΔIEC) in mice led to MASH, accompanied by intestinal barrier impairment and microbial dysbiosis [6].

In conclusion, Tm6sf2 is a significant regulator in lipid metabolism, playing key roles in various disease-related processes. Gene knockout mouse models have been instrumental in revealing its functions in diseases like MASLD-HCC, atherosclerosis, and MASH, providing valuable insights into the underlying mechanisms and potential therapeutic targets [3,4,6].

References:

1. Li, Ting-Ting, Li, Tao-Hua, Peng, Juan, Zheng, Xi-Long, Tang, Zhi-Han. 2017. TM6SF2: A novel target for plasma lipid regulation. In Atherosclerosis, 268, 170-176. doi:10.1016/j.atherosclerosis.2017.11.033. https://pubmed.ncbi.nlm.nih.gov/29232562/

2. Luo, Fei, Oldoni, Federico, Das, Avash. 2021. TM6SF2: A Novel Genetic Player in Nonalcoholic Fatty Liver and Cardiovascular Disease. In Hepatology communications, 6, 448-460. doi:10.1002/hep4.1822. https://pubmed.ncbi.nlm.nih.gov/34532996/

3. Zhang, Yating, Xie, Mingxu, Wen, Jun, Yu, Jun, Zhang, Xiang. 2025. Hepatic TM6SF2 activates antitumour immunity to suppress metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma and boosts immunotherapy. In Gut, 74, 639-651. doi:10.1136/gutjnl-2024-333154. https://pubmed.ncbi.nlm.nih.gov/39667906/

4. Zhu, Wenzhen, Liang, Wenying, Lu, Haocheng, Chen, Y Eugene, Guo, Yanhong. 2022. Myeloid TM6SF2 Deficiency Inhibits Atherosclerosis. In Cells, 11, . doi:10.3390/cells11182877. https://pubmed.ncbi.nlm.nih.gov/36139452/

5. Luo, Fei, Smagris, Eriks, Martin, Sarah A, Hobbs, Helen H, Cohen, Jonathan C. 2021. Hepatic TM6SF2 Is Required for Lipidation of VLDL in a Pre-Golgi Compartment in Mice and Rats. In Cellular and molecular gastroenterology and hepatology, 13, 879-899. doi:10.1016/j.jcmgh.2021.12.008. https://pubmed.ncbi.nlm.nih.gov/34923175/

6. Zhang, Xiang, Lau, Harry Cheuk-Hay, Ha, Suki, Wong, Vincent Wai-Sun, Yu, Jun. 2025. Intestinal TM6SF2 protects against metabolic dysfunction-associated steatohepatitis through the gut-liver axis. In Nature metabolism, 7, 102-119. doi:10.1038/s42255-024-01177-7. https://pubmed.ncbi.nlm.nih.gov/39779889/

7. Liu, Jing, Ginsberg, Henry N, Reyes-Soffer, Gissette. 2024. Basic and translational evidence supporting the role of TM6SF2 in VLDL metabolism. In Current opinion in lipidology, 35, 157-161. doi:10.1097/MOL.0000000000000930. https://pubmed.ncbi.nlm.nih.gov/38465912/

8. Chen, Li-Zhen, Xia, Harry Hua-Xiang, Xin, Yong-Ning, Lin, Zhong-Hua, Xuan, Shi-Ying. 2015. TM6SF2 E167K Variant, a Novel Genetic Susceptibility Variant, Contributing to Nonalcoholic Fatty Liver Disease. In Journal of clinical and translational hepatology, 3, 265-70. doi:10.14218/JCTH.2015.00023. https://pubmed.ncbi.nlm.nih.gov/26807382/