ArticleHepatology (Baltimore, Md.)2021
Liver-Specific Deletion of Mouse Tm6sf2 Promotes Steatosis, Fibrosis, and Hepatocellular Cancer.
Article in Hepatology (Baltimore, Md.), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers, 1 of them a synthesis that pooled it.
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Who cites it
56 citing papers in PubMed, 1 synthesis or guideline pooled it, 102 citations in OpenAlex.
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- Biomarkers for early identification of metabolic dysfunction-associated steatotic liver disease (MASLD): a narrative review.Archives of medical science : AMS · 2026Article
- Overlapping Yet Distinct Functions of Vacuole Membrane Protein 1 and Transmembrane Protein 41B in Modulating Hepatic Lipoprotein Secretion and Autophagy.Cellular and molecular gastroenterology and hepatology · 2026Article
- Pathogenesis of metabolic dysfunction-associated steatotic liver disease and donor liver damage.iLIVER · 2025Review
- Human-induced pluripotent stem cell-based hepatic modeling of lipid metabolism-associated TM6SF2-E167K variant.Hepatology (Baltimore, Md.) · 2025Article
- Metabolic Dysfunction-Associated Steatotic Liver Disease: From a Very Low-Density Lipoprotein Perspective.Biomolecules · 2025Review
- The intracellular chylomicron highway: novel insights into chylomicron biosynthesis, trafficking, and secretion.Current opinion in lipidology · 2025Review
- Walking the VLDL tightrope in cardiometabolic diseases.Trends in endocrinology and metabolism: TEM · 2025Review
- Ablation of Hepatic Asah1 Gene Disrupts Hepatic Lipid Homeostasis and Promotes Fibrotic Nonalcoholic Steatohepatitis in Mice.The American journal of pathology · 2025Article
- Molecular Regulation and Therapeutic Targeting of VLDL Production in Cardiometabolic Disease.Cellular and molecular gastroenterology and hepatology · 2025Review
- Role of Microsomal Triglyceride Transfer Protein (MTP) in Lipid Processing Pathways in Retinal Pigment Epithelium.Advances in experimental medicine and biology · 2025Article
- PNPLA3 is one of the bridges between TM6SF2 E167K variant and MASLD: Correspondence to editorial on "TM6SF2 E167K variant decreases PNPLA3-mediated PUFA transfer to promote hepatic steatosis and injury in MASLD".Clinical and molecular hepatology · 2025Article
- Clustering-based identification of immune-related gene signatures in hepatocellular carcinoma.Ecancermedicalscience · 2025Article
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
Abstract
BACKGROUND AND
aimsHuman transmembrane 6 superfamily 2 (TM6SF2) variant rs58542926 is associated with NAFLD and HCC. However, conflicting reports in germline Tm6sf2 knockout mice suggest no change or decreased very low density lipoprotein (VLDL) secretion and either unchanged or increased hepatic steatosis, with no increased fibrosis. We generated liver-specific Tm6Sf2 knockout mice (Tm6 LKO) to study VLDL secretion and the impact on development and progression of NAFLD. APPROACH AND
resultsTwo independent lines of Tm6 LKO mice exhibited spontaneous hepatic steatosis. Targeted lipidomic analyses showed increased triglyceride species whose distribution and abundance phenocopied findings in mice with liver-specific deletion of microsomal triglyceride transfer protein. The VLDL triglyceride secretion was reduced with small, underlipidated particles and unchanged or increased apolipoprotein B. Liver-specific adeno-associated viral, serotype 8 (AAV8) rescue using either wild-type or mutant E167K-Tm6 reduced hepatic steatosis and improved VLDL secretion. The Tm6 LKO mice fed a high milk-fat diet for 3 weeks exhibited increased steatosis and fibrosis, and those phenotypes were further exacerbated when mice were fed fibrogenic, high fat/fructose diets for 20 weeks. In two models of HCC, either neonatal mice injected with streptozotocin (NASH/STAM) and high-fat fed or with diethylnitrosamine injection plus fibrogenic diet feeding, Tm6 LKO mice exhibited increased steatosis, greater tumor burden, and increased tumor area versus Tm6 flox controls. Additionally, diethylnitrosamine-injected and fibrogenic diet-fed Tm6 LKO mice administered wild-type Tm6 or E167K-mutant Tm6 AAV8 revealed significant tumor attenuation, with tumor burden inversely correlated with Tm6 protein levels.
conclusionsLiver-specific Tm6sf2 deletion impairs VLDL secretion, promoting hepatic steatosis, fibrosis, and accelerated development of HCC, which was mitigated with AAV8- mediated rescue.
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