Defects in TM6SF2 Impairs Lipidation of Nascent VLDL and Leads to Accumulation of Liver Fat

Abstract

Non‐alcoholic fatty liver disease (NAFLD) is a burgeoning health problem in Western countries. Population‐based surveys indicate that one out of every three adults in the United States has excess liver fat (hepatic steatosis), the first stage of fatty liver disease. Despite the clinical importance of NAFLD, major questions remain regarding its etiology. As a step towards elucidating the pathophysiology of this disorder, we screened individuals in a population‐based study, the Dallas Heart Study (DHS) for DNA sequence variations associated with increased liver fat content. This analysis revealed that a common variant (E167K) in transmembrane 6 superfamily 2 (TM6SF2), a gene of unknown function, was associated with increased hepatic triglyceride (TG) content, reduced plasma lipid levels, and increased levels of circulating liver enzymes. TM6SF2 is expressed at highest levels in the small intestine, liver and kidney. Immunolocalization and biochemical studies localized the protein to the ER and the Golgi. To determine why individuals with the risk variant develop hepatic steatosis, we developed mice expressing no TM6SF2 (Tm6sf2−/−, KO). The Tm6sf2−/− mice have elevated levels of neutral lipids, including TG and cholesteryl esters (CE) in the liver and elevated levels of liver enzymes in the circulation, consistent with liver inflammation. At steady state the Tm6sf2−/− mice have decreased plasma levels of cholesterol and very low density lipoprotein (VLDL)‐TG. Treatment with Triton WR1339 to inhibit peripheral lipases was associated with a non‐specific and dramatic reduction in all of the VLDL associated lipid molecular species, but not apolipoprotein (Apo)‐B100. In addition, it was found that de novo synthesis of radioactive and stable labeled lipids was marginally changed in the liver, but secretion of the newly synthesized labelled lipids was dramatically decreased in the Tm6sf2−/− mouse. As expected, given these observations, VLDL was reduced in size in the KO mice. Thus, TM6SF2 plays a key role in the expansion of the nascent particle, but not in the secretion of nascent VLDL, thereby causes steatosis.Support or Funding InformationFunding was provided by the NIH through research grants R01‐DK090066 and F32‐DK112529.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.