title: TM6SF2 is a regulator of liver fat metabolism influencing triglyceride secretion and hepatic lipid droplet content.
abstract: Genome-wide association studies have identified a locus on chromosome 19 associated with plasma triglyceride (TG) concentration and nonalcoholic fatty liver disease. However, the identity and functional role of the gene(s) responsible for these associations remain unknown. Of 19 expressed genes contained in this locus, none has previously been implicated in lipid metabolism. We performed gene expression studies and expression quantitative trait locus analysis in 206 human liver samples to identify the putative causal gene. Transmembrane 6 superfamily member 2 (TM6SF2), a gene with hitherto unknown function, expressed predominantly in liver and intestine, was identified as the putative causal gene. TM6SF2 encodes a protein of 351 amino acids with 7-10 predicted transmembrane domains. Otherwise, no other protein features were identified which could help to elucidate the function of TM6SF2. Protein subcellular localization studies with confocal microscopy demonstrated that TM6SF2 is localized in the endoplasmic reticulum and the ER-Golgi intermediate compartment of human liver cells. Functional studies for secretion of TG-rich lipoproteins (TRLs) and lipid droplet content were performed in human hepatoma Huh7 and HepG2 cells using confocal microscopy and siRNA inhibition and overexpression techniques. In agreement with the genome-wide association data, it was found that TM6SF2 siRNA inhibition was associated with reduced secretion of TRLs and increased cellular TG concentration and lipid droplet content, whereas TM6SF2 overexpression reduced liver cell steatosis. We conclude that TM6SF2 is a regulator of liver fat metabolism with opposing effects on the secretion of TRLs and hepatic lipid droplet content.
authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Solna, and.
authors.forename: Hovsep
authors.initials: H
authors.lastname: Mahdessian
authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Solna, and.
authors.forename: Apostolos
authors.initials: A
authors.lastname: Taxiarchis
authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Solna, and.
authors.forename: Sergej
authors.initials: S
authors.lastname: Popov
authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Solna, and.
authors.forename: Angela
authors.initials: A
authors.lastname: Silveira
authors.affiliation: Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Franco-Cereceda
authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Solna, and.
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Solna, and.
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.affiliation: Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine, Solna, and Ferdinand.Vant.Hooft@ki.se.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: van't Hooft
mesh_terms: D000818:Animals; D002417:Cattle; D045744:Cell Line, Tumor; D004285:Dogs; D004721:Endoplasmic Reticulum / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D005838:Genotype; D006056:Golgi Apparatus / Q000378:metabolism; D006168:Guinea Pigs; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008099:Liver / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D040641:Quantitative Trait Loci; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D014018:Tissue Distribution; D014280:Triglycerides / Q000378:metabolism
chemical_list: D008055:Lipids; D008565:Membrane Proteins; D034741:RNA, Small Interfering; C419195:TM6SF2 protein, human; D014280:Triglycerides
keywords: 19p12 locus; TM6SF2 expression; TM6SF2 function; TM6SF2 identification