title: Circulating triacylglycerol signatures and insulin sensitivity in NAFLD associated with the E167K variant in TM6SF2.
abstract: OBJECTIVE
  The Glu167Lys (E167K) variant in the transmembrane 6 superfamily member 2 protein (TM6SF2) was recently shown to influence liver fat (LFAT) content. We aimed at studying how this variant influences circulating triacylglycerol (TAG) signatures and whether it influences hepatic or adipose tissue insulin sensitivity.
  
  
  METHODS
  We genotyped 300 Finnish subjects for the E167K (rs58542926) variant in TM6SF2 and for the I148M (rs738409) variant in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) in whom LFAT was measured using 1H-MRS and circulating lipids by UPLC-MS. We compared the plasma lipidome between E167K carriers (TM6SF2EK/KK) and non-carriers (TM6SF2EE), and between three groups of NAFLD: (i) carriers of the E167K but not of the I148M variant in PNPLA3 ('TM6SF2 NAFLD'), (ii) carriers of the I148M but not of the E167K variant ('PNPLA3 NAFLD'), and (iii) non-carriers of either risk allele ('Non-risk NAFLD'). Hepatic and adipose tissue insulin sensitivities were measured using the euglycemic hyperinsulinemic clamp technique combined with infusion of [3-3H]glucose in 111 subjects.
  
  
  RESULTS
  The LFAT content was 34% higher in the TM6SF2EK/KK (13.07±1.57%) than in the TM6SF2EE group (9.77±0.58%, p=0.013). The effect of insulin on glucose production and lipolysis were significantly higher in the TM6SF2EK/KK than in the TM6SF2EE group. Comparison of the three NAFLD groups with similar LFATs showed that both the 'TM6SF2 NAFLD' and 'PNPLA3 NAFLD' had significantly lower triglyceride levels and were characterized by lower levels of most common TAGs compared to the 'Non-risk NAFLD' group.
  
  
  CONCLUSIONS
  We conclude that the E167K variant in TM6SF2 is associated with a distinct subtype of NAFLD, characterized by preserved insulin sensitivity with regard to lipolysis, hepatic glucose production and lack of hypertriglyceridemia despite a clearly increased LFAT content.
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: You
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland; CIBERDEM, Endocrinology Unit, Joan XXIII University Hospital, IISPV Pere Virgili Health Research Institute, Rovira i Virgili University, Tarragona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Llauradó
authors.affiliation: Steno Diabetes Center, Niels Steensens Vej 2, 2820 Gentofte, Denmark.
authors.forename: Matej
authors.initials: M
authors.lastname: Orešič
authors.affiliation: Steno Diabetes Center, Niels Steensens Vej 2, 2820 Gentofte, Denmark.
authors.forename: Tuulia
authors.initials: T
authors.lastname: Hyötyläinen
authors.affiliation: Department of Clinical Sciences, Diabetes and Cardiovascular Disease Genetic Epidemiology, Skånes University Hospital, Lund University Diabetes Center, Lund University, Malmö, Sweden.
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Medicine, University of Helsinki, Helsinki, Finland. Electronic address: ykijarvi@cc.helsinki.fi.
authors.forename: Hannele
authors.initials: H
authors.lastname: Yki-Järvinen
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000328:Adult; D019943:Amino Acid Substitution; D005260:Female; D005387:Finland; D005787:Gene Frequency; D056726:Genetic Association Studies; D014644:Genetic Variation; D015309:Glucose Clamp Technique; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008049:Lipase / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood*; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D008049:Lipase; D008565:Membrane Proteins; D014280:Triglycerides; C419195:TM6SF2 protein, human; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
keywords: Glucose production; Lipolysis; Liver; Magnetic resonance spectroscopy; Mass spectrometry