Affinage

TM6SF2

Transmembrane 6 superfamily member 2 · UniProt Q9BZW4

Length
377 aa
Mass
42.6 kDa
Annotated
2026-06-10
84 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TM6SF2 is an endoplasmic reticulum and ER-Golgi intermediate compartment membrane protein that governs hepatic lipid mobilization for the assembly and secretion of triglyceride-rich VLDL particles (PMID:24927523, PMID:27013658). Loss of TM6SF2 in cells, mice, and rats reduces VLDL-TG secretion and causes intracellular triglyceride and lipid-droplet accumulation, yet leaves apoB secretion intact, establishing that TM6SF2 acts to lipidate nascent apoB-containing particles rather than to drive their secretion per se (PMID:24531328, PMID:27013658, PMID:33638902). Mechanistically, TM6SF2 localizes to the smooth ER where it binds apolipoprotein B-48 and ACSL5 to support bulk lipidation (PMID:34923175), and it assembles into a complex with ERLIN1/ERLIN2 in which TM6SF2 and the ERLINs mutually stabilize one another and TM6SF2 binds and stabilizes APOB through two luminal loops (PMID:32776921). TM6SF2 also directs polyunsaturated fatty acid incorporation into phosphatidylcholines and triglycerides, a function required for normal hepatic lipid synthesis (PMID:28434889, PMID:28235613). Beyond lipoprotein biology, TM6SF2 is a host factor required for ER-Golgi-dependent secretion of hepatitis B, C, and D viral particles (PMID:30144428, PMID:38408366), and in hepatocytes it binds IKKβ to suppress NF-κB/IL-6 signaling and sustain antitumor CD8+ T cell immunity, restraining MASLD-driven HCC (PMID:39667906). In intestinal epithelium TM6SF2 interacts with FABP5 to limit free fatty acid secretion, and its loss drives a gut-liver axis of dysbiosis and lysophosphatidic acid signaling that promotes MASH (PMID:39779889). The common E167K variant destabilizes TM6SF2 by accelerating its turnover, reducing protein levels, destabilizing APOB, and impairing VLDL lipidation (PMID:32776921, PMID:28449094, PMID:31406127); E167K additionally increases TM6SF2 interaction with PNPLA3 to block PUFA transfer from triglyceride to phosphatidylcholine, collectively causing steatosis, fibrosis, and elevated HCC risk (PMID:33638902, PMID:39054606).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2014 High

    Established the core question of TM6SF2 function by showing it is an ER/ERGIC protein whose loss blocks triglyceride-rich lipoprotein secretion and causes hepatocellular lipid retention.

    Evidence Confocal localization with reciprocal siRNA knockdown and overexpression in Huh7/HepG2 cells; AAV-shRNA knockdown in mice with VLDL secretion assays

    PMID:24531328 PMID:24927523

    Open questions at the time
    • Did not resolve whether the defect was in lipid loading or in particle secretion machinery
    • Molecular partners and biochemical activity unidentified
  2. 2016 High

    Resolved the step at which TM6SF2 acts by showing germline knockout reduces VLDL-TG secretion without reducing apoB secretion, separating lipidation from lipoprotein secretion.

    Evidence Germline Tm6sf2 knockout mice with VLDL-TG secretion rate measurement, fractionation, and lipid absorption assays

    PMID:27013658

    Open questions at the time
    • No binding partners or enzymatic activity defined
    • Mechanism of neutral lipid mobilization to nascent particles unknown
  3. 2017 High

    Defined the lipid-species consequences of TM6SF2 loss, linking it to PUFA incorporation into phosphatidylcholines and triglycerides and to broader metabolic remodeling.

    Evidence Stable siRNA knockdown in HuH7 cells with lipidomics, mitochondrial oxidation and EM; human liver biopsy lipidomics with PUFA incorporation assays; AAV overexpression in mice and hepatocyte protein turnover assays

    PMID:28235613 PMID:28434889 PMID:28449094

    Open questions at the time
    • Direct enzyme catalyzing PUFA transfer not identified at this stage
    • Mechanistic basis for variant protein instability not fully resolved
  4. 2020 High

    Identified the molecular complex underlying TM6SF2 function by showing it binds and is mutually stabilized by ERLIN1/2 and stabilizes APOB via luminal loops, explaining how E167K causes APOB destabilization.

    Evidence Tandem affinity purification-mass spectrometry, co-IP, luminal-loop mutagenesis, and mouse KO/Erlin knockdown with hepatic APOB measurement

    PMID:32776921

    Open questions at the time
    • Stoichiometry and structure of the TM6SF2-ERLIN-APOB complex not determined
    • How the complex couples to lipid loading mechanistically unresolved
  5. 2021 High

    Mapped TM6SF2 to the smooth ER and identified apoB-48 and ACSL5 as interacting partners, and confirmed in liver-specific KO that TM6SF2 produces underlipidated VLDL and drives steatosis, fibrosis, and HCC.

    Evidence Tm6sf2-knockout rats with perfused-liver VLDL lipid quantification and co-IP; liver-specific conditional KO mice with AAV8 rescue, lipidomics, and disease models; CRISPR KO in HepG2 with ultrastructure and mitochondrial assays

    PMID:33638902 PMID:34823063 PMID:34923175

    Open questions at the time
    • Functional role of ACSL5 interaction in lipidation not dissected
    • Causal chain from steatosis to fibrosis/HCC not fully mechanistic
  6. 2018 High

    Extended TM6SF2 function to viral pathogenesis by showing it is required for maturation, lipidation, and secretion of HCV lipoviroparticles without affecting genome replication.

    Evidence siRNA knockdown/overexpression in HCV-infected hepatocytes with density gradient fractionation, plus humanized mouse and patient biopsy data

    PMID:30144428

    Open questions at the time
    • Whether HCV co-opts the same ERLIN/APOB machinery untested
    • Direct interaction with viral components not shown
  7. 2024 Medium

    Generalized TM6SF2 as a pan-hepatitis host secretion factor for HBV, HCV, and HDV virions via the ER-Golgi pathway, with the E167K-associated genotype lowering circulating HBV subviral particles.

    Evidence siRNA knockdown across HBV/HCV/HDV cell culture models with clinical cohort polymorphism correlation

    PMID:38408366

    Open questions at the time
    • Single-lab cell-based knockdown without reciprocal validation across systems
    • Mechanism of shared secretion route not biochemically defined
  8. 2021 Medium

    Connected TM6SF2 to ER stress sensing by demonstrating interaction with IRE1α and sex-specific effects of E167K on hepatic IRE1α signaling and glucose tolerance.

    Evidence E167K knock-in mice with glucose tolerance testing, co-IP of TM6SF2 with IRE1α, and hepatic IRE1α signaling assays

    PMID:34746691

    Open questions at the time
    • Basis of sex-specificity unexplained
    • Single Co-IP for the IRE1α interaction without reciprocal/structural validation
  9. 2022 Medium

    Revealed cell-type-specific roles of TM6SF2 beyond hepatocytes, in macrophage foam-cell formation, atherosclerosis, ER stress, and de novo lipogenesis regulation.

    Evidence Myeloid-specific Tm6sf2 KO on ApoE-/- background with atherosclerosis model and macrophage KD/OE; hepatocyte KD/OE with RNA-seq and ACC inhibitor MK-4074 rescue

    PMID:35978872 PMID:36139452

    Open questions at the time
    • Molecular mechanism in macrophages not resolved to direct partners
    • Single-lab studies with gene-expression readouts
  10. 2024 Medium

    Defined a molecular mechanism for the E167K variant beyond protein instability by showing it increases TM6SF2-PNPLA3 interaction to block PUFA transfer from TG to PC, with dietary PC rescue.

    Evidence Tm6sf2 E167K knock-in mice on HFD with hepatic lipidomics, TLC, co-IP comparing WT vs E167K, and dietary PC C18:3 supplementation

    PMID:39054606

    Open questions at the time
    • Direct enzymatic role of TM6SF2 in PUFA transfer versus modulation of PNPLA3 not separated
    • Single-lab co-IP interaction mapping
  11. 2025 High

    Identified non-cell-autonomous gut-liver and immune mechanisms: intestinal TM6SF2 limits FFA secretion via FABP5 to control an LPA gut-liver axis, while hepatic TM6SF2 binds IKKβ to suppress NF-κB/IL-6 and preserve antitumor CD8+ T cell immunity.

    Evidence Intestinal-specific KO with germ-free transplant, co-housing, LPA receptor inhibitor, and FABP5 co-IP; hepatocyte-specific KO with orthotopic HCC models, IKKβ co-IP, CD8+ T cell depletion, IL-6 neutralization, and viral rescue

    PMID:39667906 PMID:39779889

    Open questions at the time
    • How a lipidation protein engages IKKβ and FABP5 mechanistically unresolved
    • Interplay between metabolic and immune functions of TM6SF2 not integrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The intrinsic biochemical activity of TM6SF2 — whether it possesses the predicted EXPERA/sterol-isomerase catalytic function or acts purely as a scaffold for lipid loading — remains undefined.
  • EXPERA-domain catalytic activity predicted computationally but never experimentally demonstrated
  • No structure of TM6SF2 or its complexes
  • Mechanistic coupling of partner binding to bulk lipidation unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-1643685 Disease 3 R-HSA-5653656 Vesicle-mediated transport 3
Partners
ACSL5APOBERLIN1ERLIN2FABP5IKBKBIRE1APNPLA3
Complex memberships
TM6SF2-ERLIN1/ERLIN2-APOB complex

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 TM6SF2 is localized in the endoplasmic reticulum and ER-Golgi intermediate compartment of human liver cells, and siRNA knockdown reduces secretion of triglyceride-rich lipoproteins while increasing intracellular triglyceride content and lipid droplet content; overexpression reduces hepatocyte steatosis. Confocal microscopy subcellular localization, siRNA knockdown, overexpression in Huh7 and HepG2 cells with lipid/TG secretion assays Proceedings of the National Academy of Sciences of the United States of America High 24927523
2014 AAV-mediated shRNA knockdown of Tm6sf2 in mice increased liver triglyceride content threefold and decreased VLDL secretion by 50%, establishing TM6SF2 as required for normal VLDL secretion in vivo; the E167K variant produces ~50% less protein when expressed in cultured hepatocytes. AAV-shRNA knockdown in mice, VLDL secretion assays, recombinant protein expression in hepatocytes Nature genetics High 24531328
2016 Genetic inactivation of Tm6sf2 in mice causes hepatic steatosis, hypocholesterolemia, and reduced VLDL-TG secretion (3-fold decrease in rate) without reduction in hepatic apoB secretion; TM6SF2 localizes to ER and Golgi; excess neutral lipids accumulate in lipid droplets distinct from TM6SF2 localization, indicating TM6SF2 is required to mobilize neutral lipids for VLDL assembly but not for apoB-containing lipoprotein secretion per se. Germline Tm6sf2 knockout mice, immunocytochemistry, cell fractionation, VLDL-TG secretion rate measurement, dietary lipid absorption assay The Journal of biological chemistry High 27013658
2021 Liver-specific Tm6sf2 knockout mice exhibit spontaneous hepatic steatosis with reduced VLDL-TG secretion, small underlipidated VLDL particles, and unchanged or increased apolipoprotein B; AAV8-mediated rescue with either wild-type or E167K-mutant Tm6sf2 reduced hepatic steatosis and improved VLDL secretion; on fibrogenic diets, Tm6sf2 LKO mice show increased steatosis, fibrosis, and accelerated HCC. Liver-specific conditional knockout mice (two independent lines), AAV8 rescue, targeted lipidomics, in vivo VLDL secretion, dietary challenge models, HCC induction models Hepatology (Baltimore, Md.) High 33638902
2021 TM6SF2 resides predominantly in smooth endoplasmic reticulum and ER-Golgi intermediate compartments (not Golgi). In Tm6sf2-knockout rats, VLDL lipid content (TG and cholesterol) from perfused livers was reduced by ~53–62%. Immunoprecipitation identified apolipoprotein B-48 and ACSL5 (acyl-CoA synthetase long chain family member 5) as TM6SF2-interacting proteins, placing TM6SF2 function at the smooth ER for bulk lipidation of apoB-containing lipoproteins. Gene-edited Tm6sf2-knockout rats, cell fractionation, perfused liver VLDL lipid quantification by mass spectrometry, co-immunoprecipitation from liver and enterocytes Cellular and molecular gastroenterology and hepatology High 34923175
2020 TM6SF2 forms a complex with ERLIN1, ERLIN2, and APOB. ERLINs and TM6SF2 mutually bind and stabilize each other. TM6SF2 binds and stabilizes APOB via two luminal loops; the E167K mutation reduces TM6SF2 protein expression, destabilizing APOB and leading to hepatic lipid accumulation and reduced serum lipid levels. Knockout of Tm6sf2 or knockdown of Erlins in mice decreases hepatic APOB protein level. Tandem affinity purification combined with mass spectrometry, co-IP, mutagenesis (luminal loop mapping), mouse Tm6sf2 KO and Erlin knockdown with hepatic lipid and APOB measurements PLoS genetics High 32776921
2017 Hepatic overexpression of Tm6sf2 in mice (via AAV) reduces plasma lipid levels and VLDL-TG secretion and increases hepatosteatosis, mirroring loss-of-function phenotype. In cultured human hepatocytes, TM6SF2 overexpression reduces apoB secretion and causes its accumulation in the ER, suggesting impaired ER-to-Golgi trafficking of pre-VLDL particles. Both E167K (rs58542926) and L156P (rs187429064) variants reduce TM6SF2 protein by increasing protein turnover rate. AAV-mediated hepatic overexpression in mice, cultured human hepatocyte apoB secretion assay, protein turnover experiments comparing variant vs. wild-type TM6SF2 Human molecular genetics High 28449094
2017 TM6SF2 knockdown in HuH7 cells results in intracellular accumulation of TAGs and cholesterol esters with depletion of polyunsaturated fatty acid species (especially arachidonic acid) in phosphatidylcholines, increased lipid synthesis and turnover, secretion of smaller lipoprotein-like particles, increased lysosome/endosome structures, and reduced mitochondrial palmitate oxidation capacity. Stable siRNA knockdown in HuH7 cells, lipidomics (lipid class and species composition), mitochondrial fatty acid oxidation assay, electron microscopy Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 28434889
2017 In human liver biopsies and TM6SF2 knockdown HuH-7 cells, TM6SF2 E167K variant carriers show decreased polyunsaturated fatty acid (PUFA) incorporation into triglycerides and phosphatidylcholines (PC), with PC deficiency and increased intrahepatic TG, demonstrating that TM6SF2 is required for hepatic lipid synthesis from PUFAs. Liver biopsies with genotyping and lipidomics, siRNA knockdown in HuH-7 cells with fatty acid incorporation assays, gene co-expression analysis Journal of hepatology High 28235613
2021 TM6SF2 silencing in HepG2 cells (via CRISPR/Cas9) alters lipid composition, induces accumulation of microvesicular lipid droplets, strongly affects ER and mitochondrial ultrastructure, increases ER and oxidative stress, increases mitochondrial number (imbalanced mitochondrial dynamics), and impairs mitochondrial activity with shift toward anaerobic glycolysis. Re-overexpression of TM6SF2 reverses these metabolic and tumorigenic features. CRISPR/Cas9 knockout in HepG2 cells, electron microscopy (ultrastructure), mitochondrial function assays, metabolic reprogramming assays, rescue overexpression Cellular and molecular gastroenterology and hepatology Medium 34823063
2018 TM6SF2 knockdown in hepatocytes reduces HCV infectious viral particle secretion and RNA levels without affecting HCV genome replication, translation, or assembly; TM6SF2 overexpression increases secretion of infectious lipoviroparticles in lower-density fractions. HCV infection upregulates TM6SF2 expression via SREBF2, and TM6SF2 is required for maturation, lipidation, and secretion of HCV lipoviroparticles. siRNA knockdown and overexpression in HCV-infected hepatocytes, iodixanol gradient density fractionation of LVPs, viral RNA/protein quantification, liver biopsies from HCV patients and humanized mice Gastroenterology High 30144428
2024 TM6SF2 knockdown in human hepatocytes reduces secretion of infectious HBV subviral particles, HCV virions, and HDV virions; carriers of the TM6SF2 rs58542926 CT/TT polymorphism have lower HBV subviral particle concentrations in blood, demonstrating TM6SF2 as a host factor required for secretion of all three hepatitis viruses via the ER-Golgi pathway. siRNA knockdown in virus cell culture models for HBV, HCV, HDV; clinical cohort correlation of TM6SF2 polymorphism with HBV subviral particle levels The Journal of infectious diseases Medium 38408366
2021 TM6SF2 interacts with IRE1α (inositol-requiring enzyme 1α), a primary ER stress sensor; male E167K knock-in mice exhibit impaired IRE1α signaling in the liver and glucose intolerance, while female KI mice do not, indicating sex-specific TM6SF2-IRE1α interaction effects on glucose metabolism. E167K knock-in mouse model, glucose tolerance testing, co-immunoprecipitation of TM6SF2 with IRE1α, hepatic IRE1α signaling assays iScience Medium 34746691
2025 Intestinal epithelial cell-specific Tm6sf2 knockout mice develop MASH; mechanistically, Tm6sf2-deficient intestinal cells secrete more free fatty acids by interacting with fatty acid-binding protein 5 (FABP5), causing intestinal barrier dysfunction, microbial dysbiosis, and elevation of lysophosphatidic acid (LPA). LPA translocates from gut to liver contributing to hepatic lipid accumulation and inflammation. Pharmacological inhibition of the LPA receptor suppresses MASH. Intestinal epithelial-specific Tm6sf2 KO mice, germ-free fecal transplant experiments, co-housing with wild-type mice, LPA measurement, LPA receptor inhibitor treatment, co-immunoprecipitation with FABP5 Nature metabolism High 39779889
2025 Hepatic TM6SF2 directly binds IKKβ and inhibits NF-κB signaling, reducing IL-6 secretion and thereby maintaining cytotoxic CD8+ T cell activity; hepatocyte-specific Tm6sf2 knockout reduces IFN-γ+ CD8+ T cells in tumors and promotes MASLD-HCC, while IL-6 neutralization abolishes the tumor-promoting effect of Tm6sf2 knockout. Hepatocyte-specific Tm6sf2 KO mice, orthotopic MASLD-HCC models, co-immunoprecipitation of TM6SF2 with IKKβ, NF-κB signaling assays, CD8+ T cell depletion, IL-6 neutralization, adenoviral TM6SF2 overexpression Gut High 39667906
2022 TM6SF2 deficiency in macrophages (myeloid-specific KO on ApoE-/- background) inhibits atherosclerosis and decreases foam cell formation without changing plasma lipids. Silencing TM6SF2 in THP-1 macrophages reduces inflammatory responses, ER stress, and cholesterol uptake; TM6SF2 is upregulated by oxLDL in macrophages; overexpression shows opposite effects. Myeloid-specific Tm6sf2 KO mice on ApoE-/- background, Western diet atherosclerosis model, RNA-seq of BMDMs, siRNA knockdown and overexpression in THP-1 macrophages with cholesterol uptake and ER stress assays Cells Medium 36139452
2023 TM6SF2 reduces lipid accumulation in vascular smooth muscle cells (VSMCs) exposed to oxLDL by downregulating expression of the scavenger receptors LOX-1 and CD36. siRNA knockdown and overexpression of TM6SF2 in HAVSMCs, lipid accumulation assay, LOX-1 and CD36 expression measurement Experimental cell research Low 37271250
2024 The TM6SF2 E167K variant increases interaction between TM6SF2 and PNPLA3, impairing PNPLA3-mediated transfer of polyunsaturated fatty acids (PUFAs) from TG to PC; this results in decreased polyunsaturated PC and increased polyunsaturated TG in liver. Dietary supplementation of PC containing C18:3 attenuates E167K-induced hepatic steatosis in HFD-fed mice. Tm6sf2 E167K knock-in mice on HFD, hepatic lipidomics, TLC for newly synthesized TG/PC, co-immunoprecipitation of TM6SF2 with PNPLA3 (comparing WT vs. E167K), dietary PC C18:3 supplementation Clinical and molecular hepatology Medium 39054606
2014 Computational sequence analysis identified a novel conserved domain (EXPERA domain) shared between TM6SF2, MAC30/TMEM97, and EBP (D8/D7 sterol isomerase) families, predicting catalytic activity as a sterol isomerase for TM6SF2 based on evolutionary conservation of predicted active-site residues. Computational protein sequence analysis, evolutionary conservation analysis, domain prediction Frontiers in genetics Low 25566323
2019 In human hepatic 3D spheroids from primary hepatocytes, the TM6SF2 E167K variant induces increased hepatocyte fat content by reducing APOB particle secretion, confirmed across five donors with inter-donor variability reflected in the model. 3D spheroid model from primary human hepatocytes with TM6SF2 E167K variant carriers vs. wild-type, APOB secretion measurement, lipid content assay Scientific reports Medium 31406127
2022 TM6SF2 deficiency (knockdown) in hepatocytes enhances fatty acid uptake and synthesis and impairs fatty acid oxidation, leading to intracellular lipid deposition. Treatment with the acetyl-CoA carboxylase inhibitor MK-4074 reverses NAFLD phenotypes caused by TM6SF2 deficiency, placing TM6SF2 upstream of de novo lipogenesis regulation. siRNA knockdown and overexpression in hepatocytes, RNA-seq, in vivo NAFLD mouse model, MK-4074 pharmacological rescue World journal of gastroenterology Medium 35978872
2024 The protective effect of the ERLIN1 p.Ile291Val variant against MASLD is not apparent in individuals carrying the TM6SF2 p.Glu167Lys variant, suggesting functional epistasis: ERLIN1 p.Ile291Val may act as a gain-of-function variant that enhances TM6SF2 function, consistent with the known ERLIN1-TM6SF2-APOB complex. Genome-first approach in UK Biobank, Penn Medicine Biobank, and All of Us cohorts; predicted loss-of-function ERLIN1 variant analysis showing opposite lipid effects; epistasis analysis with TM6SF2 E167K Med (New York, N.Y.) Low 38776916

Source papers

Stage 0 corpus · 84 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nature genetics 973 24531328
2014 TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nature communications 494 24978903
2014 TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content. Proceedings of the National Academy of Sciences of the United States of America 287 24927523
2014 Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nature genetics 239 24633158
2020 Combined Effect of PNPLA3, TM6SF2, and HSD17B13 Variants on Risk of Cirrhosis and Hepatocellular Carcinoma in the General Population. Hepatology (Baltimore, Md.) 190 32190914
2016 Inactivation of Tm6sf2, a Gene Defective in Fatty Liver Disease, Impairs Lipidation but Not Secretion of Very Low Density Lipoproteins. The Journal of biological chemistry 175 27013658
2015 Role of TM6SF2 rs58542926 in the pathogenesis of nonalcoholic pediatric fatty liver disease: A multiethnic study. Hepatology (Baltimore, Md.) 110 26457389
2017 Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers with NAFLD. Journal of hepatology 106 28235613
2021 TM6SF2: A Novel Genetic Player in Nonalcoholic Fatty Liver and Cardiovascular Disease. Hepatology communications 103 34532996
2014 Circulating triacylglycerol signatures and insulin sensitivity in NAFLD associated with the E167K variant in TM6SF2. Journal of hepatology 96 25457209
2019 The TM6SF2 E167K genetic variant induces lipid biosynthesis and reduces apolipoprotein B secretion in human hepatic 3D spheroids. Scientific reports 90 31406127
2016 Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes. Hepatology (Baltimore, Md.) 90 26822232
2021 TM6SF2/PNPLA3/MBOAT7 Loss-of-Function Genetic Variants Impact on NAFLD Development and Progression Both in Patients and in In Vitro Models. Cellular and molecular gastroenterology and hepatology 89 34823063
2015 Treating liver fat and serum triglyceride levels in NAFLD, effects of PNPLA3 and TM6SF2 genotypes: Results from the WELCOME trial. Journal of hepatology 88 26272871
2021 Liver-Specific Deletion of Mouse Tm6sf2 Promotes Steatosis, Fibrosis, and Hepatocellular Cancer. Hepatology (Baltimore, Md.) 87 33638902
2015 TM6SF2 Glu167Lys polymorphism is associated with low levels of LDL-cholesterol and increased liver injury in obese children. Pediatric obesity 69 25893821
2021 Hepatic TM6SF2 Is Required for Lipidation of VLDL in a Pre-Golgi Compartment in Mice and Rats. Cellular and molecular gastroenterology and hepatology 68 34923175
2020 Disruption of the ERLIN-TM6SF2-APOB complex destabilizes APOB and contributes to non-alcoholic fatty liver disease. PLoS genetics 51 32776921
2014 TM6SF2 and MAC30, new enzyme homologs in sterol metabolism and common metabolic disease. Frontiers in genetics 51 25566323
2015 TM6SF2 E167K variant is associated with severe steatosis in chronic hepatitis C, regardless of PNPLA3 polymorphism. Liver international : official journal of the International Association for the Study of the Liver 46 25581573
2017 Hepatic Tm6sf2 overexpression affects cellular ApoB-trafficking, plasma lipid levels, hepatic steatosis and atherosclerosis. Human molecular genetics 45 28449094
2019 Association of TM6SF2 rs58542926 T/C gene polymorphism with hepatocellular carcinoma: a meta-analysis. BMC cancer 42 31752753
2017 TM6SF2 rs58542926 variant affects postprandial lipoprotein metabolism and glucose homeostasis in NAFLD. Journal of lipid research 42 28242789
2019 TM6SF2 and MBOAT7 Gene Variants in Liver Fibrosis and Cirrhosis. International journal of molecular sciences 33 30875804
2019 Meta-analysis of the association between MBOAT7 rs641738, TM6SF2 rs58542926 and nonalcoholic fatty liver disease susceptibility. Clinics and research in hepatology and gastroenterology 29 30824369
2018 Fish intake interacts with TM6SF2 gene variant to affect NAFLD risk: results of a case-control study. European journal of nutrition 27 29574608
2017 Depletion of TM6SF2 disturbs membrane lipid composition and dynamics in HuH7 hepatoma cells. Biochimica et biophysica acta. Molecular and cell biology of lipids 27 28434889
2017 TM6SF2: A novel target for plasma lipid regulation. Atherosclerosis 27 29232562
2020 Independent and joint correlation of PNPLA3 I148M and TM6SF2 E167K variants with the risk of coronary heart disease in patients with non-alcoholic fatty liver disease. Lipids in health and disease 22 32093693
2021 PNPLA3, TM6SF2, and MBOAT7 Influence on Nutraceutical Therapy Response for Non-alcoholic Fatty Liver Disease: A Randomized Controlled Trial. Frontiers in medicine 20 34692725
2016 Meta-analysis of the influence of TM6SF2 E167K variant on Plasma Concentration of Aminotransferases across different Populations and Diverse Liver Phenotypes. Scientific reports 20 27278285
2019 Association of TM6SF2 rs58542926 gene polymorphism with the risk of non-alcoholic fatty liver disease and colorectal adenoma in Chinese Han population. BMC biochemistry 19 30727943
2019 Interaction of TM6SF2 E167K and PNPLA3 I148M variants in NAFLD in northeast China. Annals of hepatology 19 31054977
2024 TM6SF2 E167K variant decreases PNPLA3-mediated PUFA transfer to promote hepatic steatosis and injury in MASLD. Clinical and molecular hepatology 18 39054606
2021 Type 2 diabetes sex-specific effects associated with E167K coding variant in TM6SF2. iScience 16 34746691
2018 The Genetics of Clinical Liver Diseases: Insight into the TM6SF2 E167K Variant. Journal of clinical and translational hepatology 16 30271746
2025 Intestinal TM6SF2 protects against metabolic dysfunction-associated steatohepatitis through the gut-liver axis. Nature metabolism 15 39779889
2020 Association of the NCAN-TM6SF2-CILP2-PBX4-SUGP1-MAU2 SNPs and gene-gene and gene-environment interactions with serum lipid levels. Aging 15 32568739
2022 Meta-GWAS of PCSK9 levels detects two novel loci at APOB and TM6SF2. Human molecular genetics 14 34590679
2021 Lipid Droplet-Associated Factors, PNPLA3, TM6SF2, and HSD17B Proteins in Hepatopancreatobiliary Cancer. Cancers 14 34503201
2018 Coding variants in PNPLA3 and TM6SF2 are risk factors for hepatic steatosis and elevated serum alanine aminotransferases caused by a glucagon receptor antagonist. Hepatology communications 14 29761171
2025 Hepatic TM6SF2 activates antitumour immunity to suppress metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma and boosts immunotherapy. Gut 13 39667906
2022 Mechanism and therapeutic strategy of hepatic TM6SF2-deficient non-alcoholic fatty liver diseases via in vivo and in vitro experiments. World journal of gastroenterology 13 35978872
2018 TM6SF2 Promotes Lipidation and Secretion of Hepatitis C Virus in Infected Hepatocytes. Gastroenterology 13 30144428
2024 Basic and translational evidence supporting the role of TM6SF2 in VLDL metabolism. Current opinion in lipidology 12 38465912
2022 Research progress on the relationship between TM6SF2 rs58542926 polymorphism and non-alcoholic fatty liver disease. Expert review of gastroenterology & hepatology 12 35057689
2017 The additive effects of the TM6SF2 E167K and PNPLA3 I148M polymorphisms on lipid metabolism. Oncotarget 12 29088779
2016 Associations of TM6SF2 167K allele with liver enzymes and lipid profile in children: the PANIC Study. Pediatric research 11 26756786
2017 Identification of deleterious rare variants in MTTP, PNPLA3, and TM6SF2 in Japanese males and association studies with NAFLD. Lipids in health and disease 10 28950858
2022 Myeloid TM6SF2 Deficiency Inhibits Atherosclerosis. Cells 9 36139452
2017 E167K polymorphism of TM6SF2 gene affects cell cycle of hepatocellular carcinoma cell HEPA 1-6. Lipids in health and disease 9 28407767
2016 TM6SF2 E167K variant predicts severe liver fibrosis for human immunodeficiency/hepatitis C virus co-infected patients, and severe steatosis only for a non-3 hepatitis C virus genotype. World journal of gastroenterology 9 27784963
2021 Variants in PCSK7, PNPLA3 and TM6SF2 are risk factors for the development of cirrhosis in hereditary haemochromatosis. Alimentary pharmacology & therapeutics 8 33565643
2018 PNPLA3 p.I148M and TM6SF2 p.E167K variants do not predispose to liver injury in cholestatic liver diseases: A prospective analysis of 178 patients with PSC. PloS one 8 30161167
2024 The common p.Ile291Val variant of ERLIN1 enhances TM6SF2 function and is associated with protection against MASLD. Med (New York, N.Y.) 7 38776916
2021 Perturbation of TM6SF2 Expression Alters Lipid Metabolism in a Human Liver Cell Line. International journal of molecular sciences 6 34575933
2019 TM6SF2 E167K Variant Overexpression Promotes Expression of Inflammatory Cytokines in the HCC Cell Line HEPA 1-6. Journal of clinical and translational hepatology 6 30944816
2024 Human-induced pluripotent stem cell-based hepatic modeling of lipid metabolism-associated TM6SF2-E167K variant. Hepatology (Baltimore, Md.) 5 40833996
2023 TM6SF2 reduces lipid accumulation in vascular smooth muscle cells by inhibiting LOX-1 and CD36 expression. Experimental cell research 5 37271250
2022 Evaluation of the association of a variant in PNPLA3 and TM6SF2 with fibrosis progression in patients with chronic hepatitis C infection after eradication: A retrospective study. Gene 5 35143946
2022 PNPLA3 and TM6SF2 genetic variants and hepatic fibrosis and cirrhosis in Pakistani chronic hepatitis C patients: a genetic association study. BMC gastroenterology 5 36028802
2022 The TM6SF2 variant as a risk factor for hepatocellular carcinoma development in chronic liver disease patients. Clinical and experimental hepatology 5 36685261
2019 Relationship between N,N-dimethylformamide exposure, PNPLA3, GCKR, COL13A1 and TM6SF2 genes, and liver injury. Ecotoxicology and environmental safety 5 30616151
2023 Metabolic disorders induced by PNPLA3 and TM6SF2 gene variants affect chronic kidney disease in patients infected with non-genotype 3 hepatitis C virus. Lipids in health and disease 4 37400794
2018 [Effects of PNPLA3, TM6SF2 gene polymorphisms and its interactions with smoking and alcohol drinking on hepatitis B virus-associated hepatocellular carcinoma]. Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi 4 30572387
2025 PNPLA3 and TM6SF2 exacerbate the impact of alcohol and metabolic dysfunction on liver fibrosis. JHEP reports : innovation in hepatology 3 41492318
2024 G-quadruplex forming regions in GCK and TM6SF2 are targets for differential DNA methylation in metabolic disease and hepatocellular carcinoma patients. Scientific reports 3 39215018
2023 TM6SF2-rs58542926 Genetic Variant Modifies the Protective Effect of a "Prudent" Dietary Pattern on Serum Triglyceride Levels. Nutrients 3 36904112
2023 TM6SF2 Determines Both the Degree of Lipidation and the Number of VLDL Particles Secreted by the Liver. medRxiv : the preprint server for health sciences 3 37425717
2023 Effects of TM6SF2 rs58542926 polymorphism on hepatocellular lipids and insulin resistance in early type 2 diabetes. Nutrition, metabolism, and cardiovascular diseases : NMCD 3 37495452
2021 [Correlation between PNPLA3 rs738409 and TM6SF2 rs58542926 gene polymorphism and primary liver cancer in the Han Population of China's Northeast region]. Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 3 33685085
2021 Relationships among N,N-dimethylformamide exposure, CYP2E1 and TM6SF2 genes, and non-alcoholic fatty liver disease. Ecotoxicology and environmental safety 3 34794021
2025 Association between single nucleotide polymorphisms in PNPLA3, TM6SF2 and MBOAT7 genes and markers of cancer aggressiveness in a Sri Lankan NASH-related HCC cohort. BMC gastroenterology 2 40065199
2024 Deep metabolic phenotyping of humans with protein-altering variants in TM6SF2 using a genome-first approach. JHEP reports : innovation in hepatology 2 39687601
2025 Contribution of PNPLA3, GCKR, MBOAT7, NCAN, and TM6SF2 Genetic Variants to Hepatocellular Carcinoma Development in Mexican Patients. International journal of molecular sciences 1 40806538
2024 Inhibition of Cellular Factor TM6SF2 Suppresses Secretion Pathways of Hepatitis B, Hepatitis C, and Hepatitis D Viruses. The Journal of infectious diseases 1 38408366
2023 A study of genetic variants, genetic risk score and DNA methylation of PNPLA3 and TM6SF2 in alcohol liver cirrhosis. Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology 1 37589914
2023 Human Induced Pluripotent Stem Cell based Hepatic-Modeling of Lipid metabolism associated TM6SF2 E167K variant. bioRxiv : the preprint server for biology 1 38187603
2026 Analysis of PNPLA3, TM6SF2 and GCKR gene polymorphisms in patients with metabolic dysfunction-associated steatohepatitis treated with probiotics ‒ An exploratory study. Nutricion hospitalaria 0 42023869
2025 Intestinal Depletion of TM6SF2 Exacerbates High-fat Diet-induced Metabolic Dysfunction-associated Steatotic Liver Disease through the Gut-liver Axis. Journal of clinical and translational hepatology 0 40474882
2025 Impact of differential detection of TM6SF2 rs58542926 mutation in circulating tumor DNA versus peripheral blood cells on hepatocellular carcinoma patients. Discover oncology 0 40504324
2025 PNPLA3-Ile148Met and TM6SF2-Glu167Lys increase susceptibility to metabolic dysfunction-associated steatotic liver disease in children. Frontiers in endocrinology 0 41244049
2025 Genetic risk of alcohol-related liver cirrhosis: Associations of PNPLA3, TM6SF2, and a two-variant polygenic risk score. Biomolecules & biomedicine 0 41384813
2023 GDF-10 Induces an Inhibitory Effect on Epithelial-Mesenchymal Transition of Laryngeal Cancer via LPR4. Current pharmaceutical design 0 38163971

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