title: Redundant roles of the phosphatidate phosphatase family in triacylglycerol synthesis in human adipocytes.
abstract: In mammals, the evolutionary conserved family of Mg(2+)-dependent phosphatidate phosphatases (PAP1), involved in phospholipid and triacylglycerol synthesis, consists of lipin-1, lipin-2 and lipin-3. While mutations in the murine Lpin1 gene cause lipodystrophy and its knockdown in mouse 3T3-L1 cells impairs adipogenesis, deleterious mutations of human LPIN1 do not affect adipose tissue distribution. However, reduced LPIN1 and PAP1 activity has been described in participants with type 2 diabetes. We aimed to characterise the roles of all lipin family members in human adipose tissue and adipogenesis.
  
  
  
  The expression of the lipin family was analysed in adipose tissue in a cross-sectional study. Moreover, the effects of lipin small interfering RNA (siRNA)-mediated depletion on in vitro human adipogenesis were assessed.
  
  
  
  Adipose tissue gene expression of the lipin family is altered in type 2 diabetes. Depletion of every lipin family member in a human Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocyte cell line, alters expression levels of adipogenic transcription factors and lipid biosynthesis genes in early stages of differentiation. Lipin-1 knockdown alone causes a 95% depletion of PAP1 activity. Despite the reduced PAP1 activity and alterations in early adipogenesis, lipin-silenced cells differentiate and accumulate neutral lipids. Even combinatorial knockdown of lipins shows mild effects on triacylglycerol accumulation in mature adipocytes.
  
  
  
  Overall, our data support the hypothesis of alternative pathways for triacylglycerol synthesis in human adipocytes under conditions of repressed lipin expression. We propose that induction of alternative lipid phosphate phosphatases, along with the inhibition of lipid hydrolysis, contributes to the maintenance of triacylglycerol content to near normal levels.
authors.affiliation: Joan XXIII University Hospital, Pere Virgili Health Research Institut (IISPV), Modular Building, C/ Mallafre Guasch, Tarragona, 43005, Spain.|Department of Biochemistry and Molecular Biology, Rovira i Virgili University, Tarragona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Temprano
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge, CB2 0XY, UK.|, Chesterford Research Park, Little Chesterford, Saffron Walden, UK.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sembongi
authors.affiliation: Department of Food Science and the Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, NJ, USA.
authors.forename: Gil-Soo
authors.initials: GS
authors.lastname: Han
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.|Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain.|Biomedical Research Networking Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Sebastián
authors.affiliation: Biomedical Research Networking Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.|Centre for Omic Sciences, Rovira i Virgili University, Reus, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Capellades
authors.affiliation: Joan XXIII University Hospital, Pere Virgili Health Research Institut (IISPV), Modular Building, C/ Mallafre Guasch, Tarragona, 43005, Spain.|Biomedical Research Networking Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Cristóbal
authors.initials: C
authors.lastname: Moreno
authors.affiliation: Department of Pulmonary, Critical Care and Sleep Medicine, University of Louisville, Louisville, KY, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Guardiola
authors.affiliation: Division of Paediatric Endocrinology and Diabetes, Interdisciplinary Obesity Clinic, University Clinic for Child and Adolescent Medicine, University of Ulm, Ulm, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Wabitsch
authors.affiliation: Joan XXIII University Hospital, Pere Virgili Health Research Institut (IISPV), Modular Building, C/ Mallafre Guasch, Tarragona, 43005, Spain.|GEMMAIR Research Group - Applied Medicine, Department of Medicine and Surgery, Rovira i Virgili University (URV), Tarragona, Spain.
authors.forename: Cristóbal
authors.initials: C
authors.lastname: Richart
authors.affiliation: Biomedical Research Networking Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.|Centre for Omic Sciences, Rovira i Virgili University, Reus, Spain.|Department of Electronic Engineering, Rovira i Virgili University, Tarragona, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Yanes
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.|Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain.|Biomedical Research Networking Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
authors.affiliation: Department of Food Science and the Rutgers Center for Lipid Research, New Jersey Institute for Food, Nutrition and Health, Rutgers University, New Brunswick, NJ, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Carman
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/Medical Research Council Building, Hills Road, Cambridge, CB2 0XY, UK. ss560@cam.ac.uk.
authors.forename: Symeon
authors.initials: S
authors.lastname: Siniossoglou
authors.affiliation: Joan XXIII University Hospital, Pere Virgili Health Research Institut (IISPV), Modular Building, C/ Mallafre Guasch, Tarragona, 43005, Spain. mmg@mercemiranda.net.|Biomedical Research Networking Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain, . mmg@mercemiranda.net.
authors.forename: Merce
authors.initials: M
authors.lastname: Miranda
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D008060:Lipodystrophy / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D000073718:Pancreatitis-Associated Proteins; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D034741:RNA, Small Interfering; D014280:Triglycerides; C485999:LPIN1 protein, human; C584419:LPIN3 protein, human; D010711:Phosphatidate Phosphatase
keywords: Basic science; Cell lines; Human; Lipid metabolism