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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apolipoprotein B-100 / genetics*
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Cholesterol / genetics
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Cholesterol / metabolism
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Genetic Predisposition to Disease
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Genotype
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Humans
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Immunoprecipitation
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Lipid Metabolism / genetics
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Lipids / blood
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Lipids / genetics
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Membrane Proteins / genetics*
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Mice
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Mice, Knockout
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Multiprotein Complexes / genetics
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Nerve Tissue Proteins / genetics*
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Non-alcoholic Fatty Liver Disease / blood
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Non-alcoholic Fatty Liver Disease / genetics*
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Non-alcoholic Fatty Liver Disease / metabolism
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Non-alcoholic Fatty Liver Disease / pathology
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Polymorphism, Single Nucleotide / genetics
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Protein Binding / genetics
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Transfection
Substances
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APOB protein, human
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Apolipoprotein B-100
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ERLIN1 protein, human
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Lipids
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Membrane Proteins
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Multiprotein Complexes
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Nerve Tissue Proteins
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TM6SF2 protein, human
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Cholesterol
Grants and funding
This work was supported by grants from the Ministry of Science and Technology of China (2018YFA0800700 (to J.L.) and (2016YFA0500100 (to B.-L.S.)), NNSF of China (31690102 (to J.L.), 91954203 (to B.-L.S.), 31771568 (to J.L.), and 91857000 (to B.-L.S.)), 111 Project of Ministry of Education of China (B16036 (to B.-L.S.)), and Shenzhen City Technology Basic Research Program (JCYJ20170818144026198 (to B.-L.S.)). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.