title: Impaired hepatic lipid synthesis from polyunsaturated fatty acids in TM6SF2 E167K variant carriers with NAFLD.
abstract: Carriers of the transmembrane 6 superfamily member 2 E167K gene variant (TM6SF2EK/KK) have decreased expression of the TM6SF2 gene and increased risk of NAFLD and NASH. Unlike common 'obese/metabolic' NAFLD, these subjects lack hypertriglyceridemia and have lower risk of cardiovascular disease. In animals, phosphatidylcholine (PC) deficiency results in a similar phenotype. PCs surround the core of VLDL consisting of triglycerides (TGs) and cholesteryl-esters (CEs). We determined the effect of the TM6SF2 E167K on these lipids in the human liver and serum and on hepatic gene expression and studied the effect of TM6SF2 knockdown on hepatocyte handling of these lipids.
  
  
  
  Liver biopsies were taken from subjects characterized with respect to the TM6SF2 genotype, serum and liver lipidome, gene expression and histology. In vitro, after TM6SF2 knockdown in HuH-7 cells, we compared incorporation of different fatty acids into TGs, CEs, and PCs.
  
  
  
  The TM6SF2EK/KKand TM6SF2EEgroups had similar age, gender, BMI and HOMA-IR. Liver TGs and CEs were higher and liver PCs lower in the TM6SF2EK/KKthan the TM6SF2EEgroup (p<0.05). Polyunsaturated fatty acids (PUFA) were deficient in liver and serum TGs and liver PCs but hepatic free fatty acids were relatively enriched in PUFA (p<0.05). Incorporation of PUFA into TGs and PCs in TM6SF2 knockdown hepatocytes was decreased (p<0.05). Hepatic expression of TM6SF2 was decreased in variant carriers, and was co-expressed with genes regulated by PUFAs.
  
  
  
  Hepatic lipid synthesis from PUFAs is impaired and could contribute to deficiency in PCs and increased intrahepatic TG in TM6SF2 E167K variant carriers.
authors.affiliation: Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland. Electronic address: panu.luukkonen@fimnet.fi.
authors.forename: Panu K
authors.initials: PK
authors.lastname: Luukkonen
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland; Systems Immunity University Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
authors.forename: You
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: P A
authors.initials: PA
authors.lastname: Nidhina Haridas
authors.affiliation: Institute for Molecular Medicine Finland, Helsinki, Finland.
authors.forename: Om P
authors.initials: OP
authors.lastname: Dwivedi
authors.affiliation: Department of Chemistry, Örebro University, Örebro, Sweden.
authors.forename: Tuulia
authors.initials: T
authors.lastname: Hyötyläinen
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Ashfaq
authors.initials: A
authors.lastname: Ali
authors.affiliation: Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Juuti
authors.affiliation: Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Marja
authors.initials: M
authors.lastname: Leivonen
authors.affiliation: Institute for Molecular Medicine Finland, Helsinki, Finland.
authors.forename: Taru
authors.initials: T
authors.lastname: Tukiainen
authors.affiliation: Steno Diabetes Center, Gentofte, Denmark.
authors.forename: Linda
authors.initials: L
authors.lastname: Ahonen
authors.affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Scott
authors.affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Palmer
authors.affiliation: Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Arola
authors.affiliation: Lund University, Malmö, Sweden.
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.affiliation: Lund University, Malmö, Sweden.
authors.forename: Petter
authors.initials: P
authors.lastname: Vikman
authors.affiliation: Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Quentin M
authors.initials: QM
authors.lastname: Anstee
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Vesa M
authors.initials: VM
authors.lastname: Olkkonen
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
authors.forename: Matej
authors.initials: M
authors.lastname: Orešič
authors.affiliation: Institute for Molecular Medicine Finland, Helsinki, Finland; Lund University, Malmö, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.affiliation: Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Hannele
authors.initials: H
authors.lastname: Yki-Järvinen
mesh_terms: D000328:Adult; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D005260:Female; D006579:Heterozygote; D006801:Humans; D008055:Lipids / Q000096:biosynthesis*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D005231:Fatty Acids, Unsaturated; D008055:Lipids; D008079:Lipoproteins, VLDL; D008565:Membrane Proteins; C419195:TM6SF2 protein, human; D014280:Triglycerides
keywords: Arachidonic acid; Cholesterol esters; Fatty acids; Genotype; Hepatocytes; Lipogenesis; Non-alcoholic fatty liver disease; Phosphatidylcholines; Transmembrane 6 superfamily member 2; Triglycerides