Affinage

TM6SF2

Transmembrane 6 superfamily member 2 · UniProt Q9BZW4

Length
377 aa
Mass
42.6 kDa
Annotated
2026-04-28
84 papers in source corpus 21 papers cited in narrative 21 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TM6SF2 is an ER-resident polytopic membrane protein that controls the lipidation and secretion of apolipoprotein B-containing lipoproteins, with broad roles in hepatic, intestinal, and macrophage lipid metabolism, innate immune signaling, and hepatitis virus egress. In the smooth ER and ERGIC, TM6SF2 physically interacts with APOB, ACSL5, ERLIN1/2, and PNPLA3 to promote bulk neutral-lipid loading of nascent VLDL particles and the channeling of polyunsaturated fatty acids from triglycerides into phosphatidylcholines; loss of function — including the common E167K destabilizing variant — reduces VLDL-TG secretion and causes hepatic steatosis, ER stress, and progression to fibrosis and hepatocellular carcinoma (PMID:24531328, PMID:27013658, PMID:32776921, PMID:39054606). Beyond lipoprotein metabolism, TM6SF2 suppresses NF-κB/IL-6 signaling by binding IKKβ to sustain anti-tumor CD8⁺ T cell immunity in the liver, promotes cholesterol uptake and inflammatory responses in macrophages, and in intestinal epithelial cells interacts with FABP5 to regulate free fatty acid secretion and gut-barrier integrity via the lysophosphatidic acid–liver axis (PMID:39667906, PMID:36139452, PMID:39779889). TM6SF2 also facilitates ER-to-Golgi secretion of hepatitis B, C, and D virions, linking its lipid-trafficking function to the life cycles of multiple hepatotropic viruses (PMID:30144428, PMID:38408366).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2014 High

    Establishing TM6SF2 as the causal gene at the 19p13 NAFLD/dyslipidemia locus resolved a key gene-assignment question: in vivo knockdown caused hepatic steatosis and reduced VLDL secretion, while E167K reduced protein levels, defining loss-of-function as the disease mechanism.

    Evidence AAV-shRNA knockdown in mice; recombinant expression of WT vs E167K in hepatocytes; independent overexpression/knockdown mouse cohorts with serum lipid profiling

    PMID:24531328 PMID:24633158

    Open questions at the time
    • No structural data for TM6SF2 or the E167K mutation
    • Mechanism by which TM6SF2 promotes lipidation unknown
    • Tissue-specific contributions not resolved
  2. 2014 High

    Subcellular localization to the ER and ERGIC placed TM6SF2 at the site of VLDL assembly and linked its function to the early secretory pathway rather than post-Golgi trafficking.

    Evidence Confocal microscopy and cell fractionation in Huh7/HepG2 cells; siRNA/overexpression with lipoprotein secretion readouts

    PMID:24927523

    Open questions at the time
    • Whether TM6SF2 cycles between ER and ERGIC or is static was unresolved
    • Identity of direct protein partners unknown
  3. 2016 High

    Germline Tm6sf2 KO demonstrated that TM6SF2 is specifically required for neutral-lipid loading onto VLDL (reduced VLDL-TG without reduced apoB secretion), separating bulk lipidation from particle assembly.

    Evidence Germline Tm6sf2 knockout mouse with VLDL-TG secretion rates and apoB secretion measurement

    PMID:27013658

    Open questions at the time
    • How TM6SF2 mobilizes neutral lipids to VLDL remained unknown
    • Lipid species specificity not yet characterized
  4. 2017 High

    Lipidomic analyses of TM6SF2-deficient cells and E167K carrier livers revealed selective impairment of polyunsaturated fatty acid incorporation into triglycerides and phosphatidylcholines, identifying a lipid-species-specific function beyond bulk TG mobilization.

    Evidence Lipidomics of human liver biopsies from E167K carriers; fatty acid incorporation assays in TM6SF2-knockdown HuH-7 cells; membrane lipid profiling of stable KD cells

    PMID:28235613 PMID:28434889

    Open questions at the time
    • Enzymatic versus scaffolding role in PUFA channeling unclear
    • No direct enzymatic assay performed
  5. 2017 High

    Overexpression studies showed that excess TM6SF2 impairs ER-to-Golgi trafficking of APOB, and that both E167K and L156P reduce protein stability, indicating that TM6SF2 dosage — not just presence — is critical for VLDL export.

    Evidence AAV-mediated hepatic overexpression in mice; APOB trafficking in cultured hepatocytes; protein turnover of coding variants

    PMID:28449094

    Open questions at the time
    • Whether overexpression artifact or true stoichiometric requirement was debated
    • Degradation pathway of destabilized TM6SF2 not identified
  6. 2018 High

    Discovery that TM6SF2 promotes HCV lipoviroparticle secretion without affecting viral replication or assembly extended TM6SF2 function from endogenous lipoprotein export to virus egress, exploiting the same ER lipidation machinery.

    Evidence TM6SF2 knockdown/overexpression in HCV-infected hepatocytes; iodixanol gradient density profiling of secreted virions; humanized mouse validation

    PMID:30144428

    Open questions at the time
    • Whether TM6SF2 directly contacts viral proteins or acts only via lipoprotein lipidation was unclear
    • Applicability to other hepatitis viruses not tested
  7. 2020 High

    Identification of a TM6SF2–ERLIN1/2–APOB complex revealed the molecular partners through which TM6SF2 stabilizes APOB in the ER: two luminal loops of TM6SF2 bind APOB directly, while ERLINs stabilize the complex, explaining how E167K reduces APOB protein.

    Evidence Tandem affinity purification–mass spectrometry; reciprocal Co-IP; luminal loop mutagenesis; Tm6sf2 and Erlin KO mice

    PMID:32776921

    Open questions at the time
    • Stoichiometry of the complex undefined
    • Whether ERLIN-TM6SF2 interaction is constitutive or regulated unknown
    • No structural model of the complex
  8. 2021 High

    Liver-specific Tm6sf2 KO confirmed cell-autonomous hepatocyte function and showed that TM6SF2 loss promotes diet-dependent fibrosis and HCC, with rescue by AAV-delivered WT or E167K TM6SF2, establishing TM6SF2 as a liver tumor suppressor.

    Evidence Liver-specific conditional KO mice; NASH/STAM and DEN HCC models; AAV8 rescue with WT and E167K

    PMID:33638902

    Open questions at the time
    • HCC mechanism (steatosis-driven vs direct signaling) not dissected
    • Whether E167K rescue reflects residual function or dosage restoration unclear
  9. 2021 High

    Refined fractionation placed TM6SF2 in the smooth ER and ERGIC (not Golgi), and identification of ACSL5 as a physical partner linked TM6SF2 to fatty acyl-CoA metabolism at the site of VLDL lipidation.

    Evidence Cell fractionation of hepatocytes and enterocytes; immunoprecipitation identifying apoB-48 and ACSL5 as partners; Tm6sf2 KO rat model

    PMID:34923175

    Open questions at the time
    • Functional consequence of ACSL5 interaction not tested by ACSL5 perturbation
    • Whether TM6SF2 channels acyl-CoAs directly to VLDL or lipid droplets unknown
  10. 2021 High

    CRISPR knockout revealed that TM6SF2 loss disrupts ER and mitochondrial ultrastructure, increases ER/oxidative stress, shifts metabolism toward glycolysis, and promotes cell proliferation — linking TM6SF2 to organelle homeostasis and tumorigenesis beyond lipid secretion.

    Evidence CRISPR/Cas9 KO in HepG2; electron microscopy; metabolic flux analysis; rescue by re-expression; MBOAT7/TM6SF2 double KO

    PMID:34823063

    Open questions at the time
    • Whether mitochondrial phenotype is secondary to ER lipid overload or a direct TM6SF2 function unresolved
    • In vivo replication of metabolic reprogramming not performed
  11. 2022 High

    Myeloid-specific Tm6sf2 KO demonstrated a non-hepatocyte role: TM6SF2 promotes macrophage cholesterol uptake and inflammation, and its deletion reduces atherosclerosis, revealing cell-type-dependent opposing effects on disease.

    Evidence LysM-Cre myeloid-specific Tm6sf2 KO on ApoE⁻/⁻ background; Western diet atherosclerosis model; THP-1 siRNA/OE with cholesterol uptake assays

    PMID:36139452

    Open questions at the time
    • Molecular mechanism of cholesterol uptake promotion in macrophages not identified
    • Whether hepatic and macrophage functions share the same molecular partners unknown
  12. 2024 High

    Co-IP showed that E167K increases TM6SF2 interaction with PNPLA3, impairing PNPLA3-mediated PUFA transfer from TG to PC; dietary PC supplementation rescued steatosis, establishing the TM6SF2–PNPLA3 axis as a targetable lipid-remodeling pathway.

    Evidence E167K knock-in mice on HFD; Co-IP of TM6SF2 with PNPLA3; TLC of newly synthesized TG/PC; dietary rescue with C18:3-containing PC

    PMID:39054606

    Open questions at the time
    • Whether TM6SF2 directly modulates PNPLA3 catalytic activity or only proximity unknown
    • Structural basis of increased E167K–PNPLA3 interaction not determined
  13. 2024 High

    Identification of IKKβ as a TM6SF2 binding partner and demonstration that TM6SF2 suppresses NF-κB/IL-6 signaling to maintain CD8⁺ T cell anti-tumor immunity revealed a non-lipid, immunomodulatory mechanism through which TM6SF2 loss promotes HCC.

    Evidence Hepatocyte-specific Tm6sf2 KO; HFHC and DEN HCC models; Co-IP with IKKβ; IL-6 neutralization; CD8⁺ T cell depletion; adenovirus rescue

    PMID:39667906

    Open questions at the time
    • Whether IKKβ binding is direct or mediated by a complex member unclear
    • Relationship between lipid and NF-κB functions not disentangled
  14. 2024 Medium

    Extending the viral egress function, TM6SF2 knockdown suppressed secretion of HBV subviral particles and HDV virions alongside HCV, establishing TM6SF2 as a shared host factor for multiple hepatitis viruses.

    Evidence TM6SF2 knockdown in HBV, HCV, and HDV cell culture infection models; secreted particle quantification

    PMID:38408366

    Open questions at the time
    • No in vivo viral model tested
    • Whether TM6SF2 acts via a common lipidation step for all viruses or through distinct mechanisms unresolved
  15. 2025 High

    Intestinal epithelial-specific Tm6sf2 KO and germ-free fecal transplant demonstrated that TM6SF2 in enterocytes maintains gut-barrier integrity; loss increases FABP5-dependent free fatty acid secretion, microbial dysbiosis, and LPA-mediated liver injury, establishing a gut-liver axis for TM6SF2-driven MASH.

    Evidence IEC-specific Tm6sf2 KO mice; germ-free fecal microbiota transplant; Co-IP with FABP5; LPA receptor inhibition; microbiome analysis

    PMID:39779889

    Open questions at the time
    • Whether intestinal TM6SF2–FABP5 interaction governs the same PUFA-channeling seen in hepatocytes unknown
    • Contribution of intestinal vs hepatic TM6SF2 loss to human MASH not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • No high-resolution structure of TM6SF2 exists, the catalytic versus scaffolding nature of TM6SF2 in lipid remodeling is unresolved, and how its lipid-trafficking and NF-κB-suppressive functions are coordinated remains an open question.
  • No crystal or cryo-EM structure available
  • Whether TM6SF2 possesses enzymatic (e.g. sterol isomerase) activity remains untested experimentally
  • Integration of hepatocyte, macrophage, and enterocyte functions into a unified model lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 6 R-HSA-1643685 Disease 4 R-HSA-9609507 Protein localization 4 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2
Partners
ACSL5APOBERLIN1ERLIN2ERN1FABP5IKBKBPNPLA3
Complex memberships
TM6SF2–ERLIN1/2–APOB complex

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 TM6SF2 is required for normal VLDL secretion; AAV-mediated shRNA knockdown of Tm6sf2 in mice increased liver triglyceride content ~3-fold and decreased VLDL secretion by ~50%. The E167K variant produces ~50% less protein than wild-type when expressed in cultured hepatocytes, indicating the variant causes loss of function. AAV-shRNA knockdown in mice (in vivo), recombinant protein expression in cultured hepatocytes Nature genetics High 24531328
2014 TM6SF2 localizes to the endoplasmic reticulum and ER-Golgi intermediate compartment (ERGIC) of human liver cells. siRNA inhibition reduces secretion of triglyceride-rich lipoproteins (TRLs) and increases cellular triglyceride/lipid droplet content, while overexpression reduces hepatocyte steatosis. Confocal microscopy for subcellular localization; siRNA knockdown and overexpression in Huh7 and HepG2 cells with lipoprotein secretion assays Proceedings of the National Academy of Sciences of the United States of America High 24927523
2014 Transient TM6SF2 overexpression or Tm6sf2 knockdown in mice alters serum lipid profiles consistent with human association data, confirming TM6SF2 as the functional gene at the 19p13 locus influencing total cholesterol. In vivo mouse overexpression and knockdown experiments with serum lipid profiling Nature genetics High 24633158
2016 Genetic inactivation of Tm6sf2 in mice causes hepatic steatosis, hypocholesterolemia, and transaminitis. TM6SF2 protein localizes to the ER and Golgi complex. VLDL-TG secretion is reduced ~3-fold without reduction in apoB secretion, indicating TM6SF2 is required to mobilize neutral lipids for VLDL lipidation but not for apoB-containing lipoprotein particle secretion per se. Excess lipids accumulate in lipid droplets. Germline Tm6sf2 knockout mouse; immunocytochemistry; cell fractionation; VLDL-TG secretion rate measurement; apoB secretion assay The Journal of biological chemistry High 27013658
2017 Hepatic Tm6sf2 overexpression in mice reduces plasma lipid levels and hepatic TG secretion and increases hepatosteatosis, recapitulating the KO phenotype. In cultured human hepatocytes, Tm6sf2 overexpression reduces apolipoprotein B secretion and causes APOB accumulation within the ER, suggesting impaired ER-to-Golgi trafficking of pre-VLDL particles. Both E167K and L156P coding variants affect TM6SF2 protein stability (altered protein turnover). AAV-mediated hepatic overexpression in mice; APOB trafficking assay in cultured hepatocytes; protein turnover analysis of coding variants Human molecular genetics High 28449094
2020 TM6SF2 forms a complex with ERLIN1, ERLIN2, and APOB (identified by tandem affinity purification/mass spectrometry). ERLINs and TM6SF2 mutually stabilize each other. TM6SF2 binds and stabilizes APOB via two luminal loops. ERLINs stabilize APOB indirectly through TM6SF2. The E167K mutation reduces TM6SF2 protein expression and thereby destabilizes APOB. Knockout of Tm6sf2 or Erlins in mice decreases hepatic APOB protein, causing hepatic lipid accumulation and lower serum lipids. Tandem affinity purification + mass spectrometry; Co-IP; mutagenesis of TM6SF2 luminal loops; Tm6sf2 and Erlin knockdown/KO in mice PLoS genetics High 32776921
2021 Liver-specific Tm6sf2 knockout (Tm6sf2 LKO) mice develop spontaneous hepatic steatosis with VLDL-TG secretion reduced and small, underlipidated VLDL particles produced with unchanged or increased apoB. Feeding fibrogenic diets exacerbates steatosis and fibrosis, and promotes HCC. AAV8-mediated rescue with either wild-type or E167K-mutant Tm6sf2 reduces hepatic steatosis and restores VLDL secretion, and attenuates tumor burden. Liver-specific conditional KO mice; targeted lipidomics; VLDL-TG secretion assay; AAV8 rescue; HCC models (NASH/STAM and DEN injection) Hepatology (Baltimore, Md.) High 33638902
2021 TM6SF2 is present predominantly in the smooth ER and ERGIC (not Golgi) of hepatocytes and enterocytes, determined by cell fractionation. TM6SF2 acts in the smooth ER to promote bulk lipidation of apoB-containing lipoproteins. By immunoprecipitation, both apolipoprotein B-48 and acyl-CoA synthetase long chain family member 5 (ACSL5) physically interact with TM6SF2. Cell fractionation; immunoprecipitation; Tm6sf2-/- rat model; perfused liver VLDL lipid content assay; mass spectrometry identification of interacting proteins Cellular and molecular gastroenterology and hepatology High 34923175
2017 TM6SF2 knockdown in HuH7 hepatoma cells alters membrane lipid composition: accumulation of TAGs, cholesterol esters, PC, and PE, with selective depletion of polyunsaturated lipid species (especially arachidonic acid) and increase in saturated/monounsaturated species. Mitochondrial capacity for palmitate oxidation is significantly reduced. Secreted lipoprotein-like particles are smaller in KD cells. Stable siRNA knockdown in HuH7 cells; lipidomic analysis; mitochondrial fatty acid oxidation assay; lipoprotein particle sizing Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 28434889
2017 TM6SF2 E167K carrier hepatocytes show impaired incorporation of polyunsaturated fatty acids (PUFAs) into triglycerides and phosphatidylcholines (PCs). Liver biopsies from E167K carriers have higher TG and CE but lower PC levels, with PUFA deficiency in liver and serum TGs and liver PCs. TM6SF2 knockdown in HuH-7 cells recapitulates reduced PUFA incorporation into TGs and PCs. Liver biopsies with lipidomic analysis; TM6SF2 knockdown in HuH-7 cells with fatty acid incorporation assay; gene expression analysis Journal of hepatology High 28235613
2018 TM6SF2 promotes lipidation and secretion of hepatitis C virus lipoviroparticles (LVPs). TM6SF2 knockdown in hepatocytes reduces HCV RNA and infectious LVP secretion without affecting HCV replication, translation, or assembly. TM6SF2 overexpression increases LVP secretion into culture supernatant in lower-density fractions. HCV infection upregulates TM6SF2 expression via SREBF2. TM6SF2 knockdown and overexpression in hepatic cells; iodixanol gradient assay for LVP density; HCV infection assay; measurement of viral RNA and infectious titers; humanized mouse and patient biopsy analysis Gastroenterology High 30144428
2021 TM6SF2 CRISPR/Cas9 silencing in HepG2 cells alters lipid composition, induces accumulation of microvesicular lipid droplets, disrupts ER and mitochondrial ultrastructure, increases ER/oxidative stress, and increases mitochondrial number (reflecting imbalanced mitochondrial dynamics). Double knockout of MBOAT7 and TM6SF2 impairs mitochondrial activity with a shift toward anaerobic glycolysis and increases cell proliferation rate. Re-overexpression of TM6SF2 reverses these metabolic and tumorigenic features. CRISPR/Cas9 knockout in HepG2 cells; electron microscopy of ER/mitochondria ultrastructure; lipidomics; metabolic flux analysis; rescue by re-expression Cellular and molecular gastroenterology and hepatology High 34823063
2021 TM6SF2 interacts with inositol-requiring enzyme 1α (IRE1α), a primary ER stress sensor. Male E167K knock-in mice exhibit impaired glucose tolerance and impaired IRE1α signaling in the liver, while female KI mice are unaffected, linking TM6SF2 to ER stress regulation in a sex-specific manner. E167K knock-in mouse model; glucose tolerance tests; Co-IP of TM6SF2 with IRE1α; hepatic IRE1α signaling assays iScience Medium 34746691
2022 Myeloid-specific Tm6sf2 knockout (on ApoE-/- background) inhibits atherosclerosis and reduces foam cell formation without changing plasma lipid profiles. TM6SF2 silencing in macrophages reduces inflammatory responses, ER stress, cholesterol uptake, and foam cell formation; overexpression has opposite effects. TM6SF2 is upregulated by oxidized LDL in macrophages. Myeloid-specific Tm6sf2 KO mice (LysM-Cre); Western diet atherosclerosis model; RNA-seq of BMDMs; THP-1 macrophage siRNA/OE experiments; cholesterol uptake and foam cell assays Cells High 36139452
2023 TM6SF2 reduces lipid accumulation in vascular smooth muscle cells (VSMCs) by downregulating LOX-1 (lectin-like oxLDL receptor 1) and CD36 (scavenger receptor) expression in response to oxLDL stimulation. siRNA knockdown and overexpression of TM6SF2 in human aortic VSMCs; lipid accumulation assay; LOX-1 and CD36 expression analysis Experimental cell research Medium 37271250
2024 The TM6SF2 E167K variant increases the interaction between TM6SF2 and PNPLA3, and impairs PNPLA3-mediated transfer of polyunsaturated fatty acids (PUFAs) from triglycerides to phosphatidylcholines (PCs). E167K KI mice on HFD show decreased polyunsaturated PC and increased polyunsaturated TG. Dietary supplementation with PC containing C18:3 attenuates E167K-induced hepatic steatosis in HFD mice. Tm6sf2 E167K knock-in mice; hepatic lipidomics; thin-layer chromatography of newly synthesized TG/PC; Co-IP of TM6SF2 with PNPLA3; dietary rescue experiment Clinical and molecular hepatology High 39054606
2024 TM6SF2 directly binds IKKβ and inhibits NF-κB signaling, thereby reducing IL-6 secretion from hepatocytes. This mechanism activates cytotoxic CD8+ T cells and suppresses MASLD-related HCC. Hepatocyte-specific Tm6sf2 KO increases IL-6 and reduces IFN-γ+CD8+ T cells in tumors; IL-6 neutralization abolishes the tumor-promoting effect of Tm6sf2 KO. Hepatocyte-specific Tm6sf2 KO mice; HFHC diet and DEN-induced HCC models; orthotopic HCC model; Co-IP of TM6SF2 with IKKβ; IL-6 neutralization; CD8+ T cell depletion; adenovirus-mediated rescue Gut High 39667906
2025 Intestinal epithelial cell-specific Tm6sf2 knockout (Tm6sf2ΔIEC) mice develop MASH accompanied by impaired intestinal barrier and microbial dysbiosis. Stool transplant from Tm6sf2ΔIEC mice induces steatohepatitis in germ-free recipients. Mechanistically, Tm6sf2-deficient intestinal cells interact with fatty acid-binding protein 5 (FABP5) to secrete more free fatty acids, causing gut barrier dysfunction and enrichment of pathobionts. This elevates lysophosphatidic acid (LPA) that translocates to the liver to promote lipid accumulation and inflammation. Intestinal-specific Tm6sf2 KO mice; germ-free fecal transplant; co-housing rescue; Co-IP with FABP5; LPA receptor pharmacological inhibition; gut microbiome analysis Nature metabolism High 39779889
2024 In iPSC-derived hepatocytes carrying the TM6SF2 E167K mutation, TM6SF2 protein expression is decreased, intracellular lipid droplets and total cholesterol are increased, and VLDL secretion is reduced. Signs of ER stress and mitochondrial dysfunction are observed. Facilitating protein folding within the ER of E167K hepatocytes improves VLDL secretion and reduces ER stress markers. CRISPR gene editing of iPSCs; hepatocyte-directed differentiation; lipidomics; transcriptomics; ER chaperone treatment rescue experiment Hepatology (Baltimore, Md.) Medium 40833996
2024 Inhibition (knockdown) of TM6SF2 in viral hepatitis cell culture models suppresses secretion of infectious HCV virions, HDV virions, and HBV subviral particles, indicating TM6SF2 functions in the ER-Golgi secretion pathway exploited by multiple hepatitis viruses. TM6SF2 knockdown in HBV, HCV, HDV cell culture infection models; measurement of secreted infectious particles and subviral particles; correlation with human cohort polymorphism data The Journal of infectious diseases Medium 38408366
2014 Computational sequence analysis identified a conserved EXPERA domain shared among TM6SF2, MAC30/TMEM97, and EBP (D8/D7 sterol isomerase) protein families, predicting that TM6SF2 may possess catalytic activity as a sterol isomerase. Computational protein sequence analysis and evolutionary conservation analysis Frontiers in genetics Low 25566323

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 962 24531328
2014 TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease. Nature communications 485 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 284 24927523
2014 Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. Nature genetics 236 24633158
2020 Combined Effect of PNPLA3, TM6SF2, and HSD17B13 Variants on Risk of Cirrhosis and Hepatocellular Carcinoma in the General Population. Hepatology (Baltimore, Md.) 187 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 173 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 101 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 89 31406127
2016 Diverse impacts of the rs58542926 E167K variant in TM6SF2 on viral and metabolic liver disease phenotypes. Hepatology (Baltimore, Md.) 89 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 88 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 87 26272871
2021 Liver-Specific Deletion of Mouse Tm6sf2 Promotes Steatosis, Fibrosis, and Hepatocellular Cancer. Hepatology (Baltimore, Md.) 85 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 66 34923175
2014 TM6SF2 and MAC30, new enzyme homologs in sterol metabolism and common metabolic disease. Frontiers in genetics 51 25566323
2020 Disruption of the ERLIN-TM6SF2-APOB complex destabilizes APOB and contributes to non-alcoholic fatty liver disease. PLoS genetics 48 32776921
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 16 39054606
2018 The Genetics of Clinical Liver Diseases: Insight into the TM6SF2 E167K Variant. Journal of clinical and translational hepatology 16 30271746
2021 Type 2 diabetes sex-specific effects associated with E167K coding variant in TM6SF2. iScience 15 34746691
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
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 Intestinal TM6SF2 protects against metabolic dysfunction-associated steatohepatitis through the gut-liver axis. Nature metabolism 13 39779889
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
2021 Lipid Droplet-Associated Factors, PNPLA3, TM6SF2, and HSD17B Proteins in Hepatopancreatobiliary Cancer. Cancers 13 34503201
2018 TM6SF2 Promotes Lipidation and Secretion of Hepatitis C Virus in Infected Hepatocytes. Gastroenterology 13 30144428
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
2024 Basic and translational evidence supporting the role of TM6SF2 in VLDL metabolism. Current opinion in lipidology 11 38465912
2016 Associations of TM6SF2 167K allele with liver enzymes and lipid profile in children: the PANIC Study. Pediatric research 11 26756786
2025 Hepatic TM6SF2 activates antitumour immunity to suppress metabolic dysfunction-associated steatotic liver disease-related hepatocellular carcinoma and boosts immunotherapy. Gut 10 39667906
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.) 6 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
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
2024 Human-induced pluripotent stem cell-based hepatic modeling of lipid metabolism-associated TM6SF2-E167K variant. Hepatology (Baltimore, Md.) 4 40833996
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
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 4 35143946
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
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 reduces lipid accumulation in vascular smooth muscle cells by inhibiting LOX-1 and CD36 expression. Experimental cell research 3 37271250
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 PNPLA3 and TM6SF2 exacerbate the impact of alcohol and metabolic dysfunction on liver fibrosis. JHEP reports : innovation in hepatology 2 41492318
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 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 1 40065199
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 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 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 0 37589914
2023 GDF-10 Induces an Inhibitory Effect on Epithelial-Mesenchymal Transition of Laryngeal Cancer via LPR4. Current pharmaceutical design 0 38163971