title: Hepatic Transmembrane 6 Superfamily Member 2 Regulates Cholesterol Metabolism in Mice.
abstract: The rs58542926 C>T variant of the transmembrane 6 superfamily member 2 gene (TM6SF2), encoding an E167K amino acid substitution, has been correlated with reduced total cholesterol (TC) and cardiovascular disease. However, little is known about the role of TM6SF2 in metabolism. We investigated the long-term effects of altered TM6SF2 levels in cholesterol metabolism.
  
  
  
  C57BL/6 mice (controls), mice that expressed TM6SF2 specifically in the liver, and mice with CRISPR/Cas9-mediated knockout of Tm6sf2 were fed chow or high-fat diets. Blood samples were collected from all mice and plasma levels of TC, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol, and triglycerides were measured. Liver tissues were collected and analyzed by histology, real-time polymerase chain reaction, and immunoblot assays. Adenovirus vectors were used to express transgenes in cultured Hep3B hepatocytes.
  
  
  
  Liver-specific expression of TM6SF2 increased plasma levels of TC and LDL-c, compared with controls, and altered liver expression of genes that regulate cholesterol metabolism. Tm6sf2-knockout mice had decreased plasma levels of TC and LDL-c, compared with controls, and consistent changes in expression of genes that regulate cholesterol metabolism. Expression of TM6SF2 promoted cholesterol biosynthesis in hepatocytes.
  
  
  
  TM6SF2 regulates cholesterol metabolism in mice and might be a therapeutic target for cardiovascular disease.
authors.affiliation: Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Haocheng
authors.initials: H
authors.lastname: Lu
authors.affiliation: Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Tianqing
authors.initials: T
authors.lastname: Zhu
authors.affiliation: Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia.
authors.forename: Minerva T
authors.initials: MT
authors.lastname: Garcia-Barrio
authors.affiliation: Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, China.
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan; Department of Human Genetics, University of Michigan, Ann Arbor, Michigan; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Cristen J
authors.initials: CJ
authors.lastname: Willer
authors.affiliation: Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Cardiovascular Center, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan. Electronic address: echenum@umich.edu.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chen
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D002460:Cell Line; D002784:Cholesterol / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D059305:Diet, High-Fat; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D013997:Time Factors; D014162:Transfection; D014280:Triglycerides / Q000097:blood
chemical_list: D015415:Biomarkers; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D008565:Membrane Proteins; C419195:TM6SF2 protein, human; D014280:Triglycerides; D002784:Cholesterol
keywords: Gene Regulation; Lipid Disorder; Membrane Proteins; Translational Research