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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver disorders affecting 20–30% of adults worldwide and higher of certain ethnic groups [1]
Non-alcoholic fatty liver disease (NAFLD) is a very common liver disorder that occurs in people who do not drink too much alcohol
NAFLD is often associated with other health problems such as obesity, diabetes, and hyperlipidemia
Summary
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver disorders affecting 20–30% of adults worldwide and higher of certain ethnic groups [1] It covers a wide degree of liver damage, including simple fat deposition (steatosis), inflammation (non-alcoholic steatohepatitis), and scarring (fibrosis and cirrhosis) [2,3,4]. TM6SF2 is a transmembrane protein mainly localized in the endoplasmic reticulum (ER), ER-Golgi intermediate compartment and Golgi of hepatocytes and enterocytes [12, 13]. It critically regulates lipid metabolism in the liver [11]. The exact roles of TM6SF2 in APOB metabolism and NAFLD remain unclear
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