title: Transmembrane protein 55B is a novel regulator of cellular cholesterol metabolism.
abstract: OBJECTIVE
  Interindividual variation in pathways affecting cellular cholesterol metabolism can influence levels of plasma cholesterol, a well-established risk factor for cardiovascular disease. Inherent variation among immortalized lymphoblastoid cell lines from different donors can be leveraged to discover novel genes that modulate cellular cholesterol metabolism. The objective of this study was to identify novel genes that regulate cholesterol metabolism by testing for evidence of correlated gene expression with cellular levels of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) mRNA, a marker for cellular cholesterol homeostasis, in a large panel of lymphoblastoid cell lines.
  
  
  RESULTS
  Expression array profiling was performed on 480 lymphoblastoid cell lines established from participants of the Cholesterol and Pharmacogenetics (CAP) statin clinical trial, and transcripts were tested for evidence of correlated expression with HMGCR as a marker of intracellular cholesterol homeostasis. Of these, transmembrane protein 55b (TMEM55B) showed the strongest correlation (r=0.29; P=4.0E-08) of all genes not previously implicated in cholesterol metabolism and was found to be sterol regulated. TMEM55B knockdown in human hepatoma cell lines promoted the decay rate of the low-density lipoprotein receptor, reduced cell surface low-density lipoprotein receptor protein, impaired low-density lipoprotein uptake, and reduced intracellular cholesterol.
  
  
  CONCLUSIONS
  Here, we report identification of TMEM55B as a novel regulator of cellular cholesterol metabolism through the combination of gene expression profiling and functional studies. The findings highlight the value of an integrated genomic approach for identifying genes that influence cholesterol homeostasis.
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.). mwmedina@chori.org.
authors.forename: Marisa W
authors.initials: MW
authors.lastname: Medina
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.).
authors.forename: Frederick
authors.initials: F
authors.lastname: Bauzon
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.).
authors.forename: Devesh
authors.initials: D
authors.lastname: Naidoo
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.).
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Theusch
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.).
authors.forename: Kristen
authors.initials: K
authors.lastname: Stevens
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.).
authors.forename: Jessica
authors.initials: J
authors.lastname: Schilde
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.).
authors.forename: Christian
authors.initials: C
authors.lastname: Schubert
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.).
authors.forename: Lara M
authors.initials: LM
authors.lastname: Mangravite
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.).
authors.forename: Lawrence L
authors.initials: LL
authors.lastname: Rudel
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.).
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Temel
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.).
authors.forename: Heiko
authors.initials: H
authors.lastname: Runz
authors.affiliation: From the Children's Hospital Oakland Research Institute, CA (M.W.M., F.B., D.N., E.T., K.S., R.M.K.); Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany (J.S., H.R.); Sage Bionetworks, Seattle, WA (L.M.M.); Section on Lipid Sciences, Department of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC (L.L.R., R.E.T.); and Molecular Medicine Partnership Unit (MMPU), Heidelberg, Germany (C.S., H.R.).
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Krauss
mesh_terms: D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D020869:Gene Expression Profiling; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis / Q000235:genetics; D007424:Intracellular Fluid / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008214:Lymphocytes / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011973:Receptors, LDL / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D011973:Receptors, LDL; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases
keywords: cardiovascular diseases; cholesterol; low-density lipoprotein receptor, human; phosphatidylinositol 4,5-diphosphate