title: Pleiotropic Effect of Human ApoE4 on Cerebral Ceramide and Saturated Fatty Acid Levels.
abstract: BACKGROUND
  Apolipoprotein E (ApoE) is known for its role in lipid trafficking and the ɛ4 allele is a risk factor for late onset Alzheimer's disease (AD). Recently, aberrant ceramide and fatty acid (FA) levels have been implicated in AD.
  
  
  OBJECTIVE
  To determine the specific effects of human ApoE4 (hE4) on cerebral ceramide and FA content during chow or a high fat/high cholesterol (HFHC) diet.
  
  
  METHODS
  Cerebral ceramide and FA profiles were determined by LC-MSMS in 15-month-old female wild-type (WT), ApoE-knockout (E0), and hE4-knockin mice fed chow or a HFHC diet for 3 months. mRNA levels of genes involved in ceramide and FA metabolism were determined by qPCR.
  
  
  RESULTS
  Similar to E0, hE4 mice displayed lower cerebral total ceramide, Cer16 : 0, and Cer24 : 1 levels than WT mice on both diets. Akin to WT mice, hE4 mice had lower total and saturated FA levels on chow than E0 mice. The HFHC diet significantly increased total and saturated FA levels in hE4 mice. Chow-fed hE4 mice showed lower mRNA levels of ceramide synthase (CerS) 6, acid sphingomyelinase, and of most ceramide and FA transporters than WT and E0 mice. The HFHC diet downregulated the expression of CerSs in hE4 and WT mice, and of ceramide and FA transporters in WT mice, but not in E0 mice.
  
  
  CONCLUSIONS
  hE4 reduced cerebral ceramide levels to levels observed in E0 mice independent of diet. The HFHC diet increased cerebral FA levels in hE4 mice. This was associated with alterations in the expression of ceramide and FA transporters specifically in hE4 mice.
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Sandra
authors.initials: S
authors.lastname: den Hoedt
authors.affiliation: Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Carola I F
authors.initials: CIF
authors.lastname: Janssen
authors.affiliation: Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington DC, USA.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Astarita
authors.affiliation: Department of Pharmacology, University of California Irvine, CA, USA.
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Frank P J
authors.initials: FPJ
authors.lastname: Leijten
authors.affiliation: Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Crivelli
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Adrie J M
authors.initials: AJM
authors.lastname: Verhoeven
authors.affiliation: Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
authors.affiliation: Department of Neurology, University of Bonn, Bonn, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Walter
authors.affiliation: Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
authors.forename: Pilar
authors.initials: P
authors.lastname: Martinez-Martinez
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Eric J G
authors.initials: EJG
authors.lastname: Sijbrands
authors.affiliation: Department of Anatomy, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Kiliaan
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Monique T
authors.initials: MT
authors.lastname: Mulder
mesh_terms: D000818:Animals; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002518:Ceramides / Q000378:metabolism*; D059305:Diet, High-Fat; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation
chemical_list: D053327:Apolipoprotein E4; D002518:Ceramides; D005227:Fatty Acids; D012333:RNA, Messenger
keywords: Alzheimer’s disease; apolipoprotein E4; ceramides; fatty acids; high fat 
  diet; sphingolipids