ArticlePLoS genetics2020
Disruption of the ERLIN-TM6SF2-APOB complex destabilizes APOB and contributes to non-alcoholic fatty liver disease.
Article in PLoS genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 57 citations in OpenAlex.
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- Genetic Impacts on Variability of Body Fat Distribution Uncover Gene-Environment and Gene-Gene Interactions.bioRxiv : the preprint server for biology · 2026Article
- Modeling Transmembrane 6 Superfamily Member 2 p.Glu167Lys-associated Steatotic Liver Disease Using Androgen-treated Human Induced Pluripotent Stem Cell-derived Hepatocyte-like Cells.Gastro hep advances · 2026Article
- Human genetics of metabolic dysfunction-associated steatotic liver disease: from variants to cause to precision treatment.The Journal of clinical investigation · 2025Review
- Trans-ancestral rare variant association study with machine learning-based phenotyping for metabolic dysfunction-associated steatotic liver disease.Genome biology · 2025Article
- Precision medicine and nucleotide-based therapeutics to treat steatotic liver disease.Clinical and molecular hepatology · 2025Review
- Molecular Regulation and Therapeutic Targeting of VLDL Production in Cardiometabolic Disease.Cellular and molecular gastroenterology and hepatology · 2025Review
- Deep metabolic phenotyping of humans with protein-altering variants inJHEP reports : innovation in hepatology · 2025Article
- Rab2A-mediated Golgi-lipid droplet interactions support very-low-density lipoprotein secretion in hepatocytes.The EMBO journal · 2024Article
- Genetics of Metabolic Dysfunction-associated Steatotic Liver Disease: The State of the Art Update.Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association · 2024Review
- TM6SF2 E167K variant decreases PNPLA3-mediated PUFA transfer to promote hepatic steatosis and injury in MASLD.Clinical and molecular hepatology · 2024Article
- The contribution of genetics and epigenetics to MAFLD susceptibility.Hepatology international · 2024Review
- Multi-ancestry polygenic mechanisms of type 2 diabetes.Nature medicine · 2024Article
- Pla2g12b drives expansion of triglyceride-rich lipoproteins.Nature communications · 2024Article
- Interaction models matter: an efficient, flexible computational framework for model-specific investigation of epistasis.BioData mining · 2024Article
- VLDL Biogenesis and Secretion: It Takes a Village.Circulation research · 2024Review
- Unlocking the mysteries of VLDL: exploring its production, intracellular trafficking, and metabolism as therapeutic targets.Lipids in health and disease · 2024Article
- Lysosomal cholesterol accumulation is commonly found in most peroxisomal disorders and reversed by 2-hydroxypropyl-β-cyclodextrin.Science China. Life sciences · 2023Article
- Cargo Receptor-Mediated ER Export in Lipoprotein Secretion and Lipid Homeostasis.Cold Spring Harbor perspectives in biology · 2023Review
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder characterized by excess lipid accumulation in the liver without significant consumption of alcohol. The transmembrane 6 superfamily member 2 (TM6SF2) E167K missense variant strongly associates with NAFLD in humans. The E167K mutation destabilizes TM6SF2, resulting in hepatic lipid accumulation and low serum lipid levels. However, the molecular mechanism by which TM6SF2 regulates lipid metabolism remains unclear. By using tandem affinity purification in combination with mass spectrometry, we found that apolipoprotein B (APOB), ER lipid raft protein (ERLIN) 1 and 2 were TM6SF2-interacting proteins. ERLINs and TM6SF2 mutually bound and stabilized each other. TM6SF2 bound and stabilized APOB via two luminal loops. ERLINs did not interact with APOB directly but still increased APOB stability through stabilizing TM6SF2. This APOB stabilization was hampered by the E167K mutation that reduced the protein expression of TM6SF2. In mice, knockout of Tm6sf2 and knockdown of Tm6sf2 or Erlins decreased hepatic APOB protein level, causing lipid accumulation in the liver and lowering lipid levels in the serum. We conclude that defective APOB stabilization, as a result of ERLINs or TM6SF2 deficiency or E167K mutation, is a key factor contributing to NAFLD.
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