Tm6sf2, or Transmembrane 6 superfamily 2, is located on chromosome 19 (19p12) and its function is related to regulating plasma lipids. It is involved in lipid metabolism pathways, such as intestinal cholesterol absorption, hepatic cholesterol biosynthesis and transport, and the lipidation of very-low-density lipoproteins (VLDL) [1,5,6]. It has been recognized as a potential therapeutic target for cardiovascular disease and is associated with non-alcoholic fatty liver disease (NAFLD) [1,2]. 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 gene-knockout studies, hepatocyte-specific Tm6sf2 knockout mice showed exacerbated tumour formation in metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma (MASLD-HCC) models, along with a reduction in interferon-gamma (IFN-γ)+CD8+ T cells, suggesting that Tm6sf2 can promote antitumour immunity via the NF-κB-IL-6 axis [3]. Myeloid cell-specific Tm6sf2 knockout mice on an ApoE-deficient background had inhibited atherosclerosis and decreased foam cells in plaques, with down-regulation of genes related to inflammation, cholesterol uptake, and endoplasmic reticulum stress [4]. Tm6sf2-/-rats and mice had higher hepatic triglyceride content, lower plasma cholesterol levels, and reduced lipid content in newly secreted VLDLs, indicating that Tm6sf2 is required for the lipidation of VLDL in the smooth endoplasmic reticulum [5].

In conclusion, Tm6sf2 is a key regulator in plasma lipid metabolism. Gene-knockout mouse models have been instrumental in revealing its role in diseases such as MASLD-HCC and atherosclerosis, highlighting its potential as a therapeutic target for these disease areas.