title: Plasma cholesteryl ester transfer protein is predominantly derived from Kupffer cells.
abstract: The role of Kupffer cells (KCs) in the pathophysiology of the liver has been firmly established. Nevertheless, KCs have been underexplored as a target for diagnosis and treatment of liver diseases owing to the lack of noninvasive diagnostic tests. We addressed the hypothesis that cholesteryl ester transfer protein (CETP) is mainly derived from KCs and may predict KC content. Microarray analysis of liver and adipose tissue biopsies, obtained from 93 obese subjects who underwent elective bariatric surgery, showed that expression of CETP is markedly higher in liver than adipose tissue. Hepatic expression of CETP correlated strongly with that of KC markers, and CETP messenger RNA and protein colocalized specifically with KCs in human liver sections. Hepatic KC content as well as hepatic CETP expression correlated strongly with plasma CETP concentration. Mechanistic and intervention studies on the role of KCs in determining the plasma CETP concentration were performed in a transgenic (Tg) mouse model expressing human CETP. Selective elimination of KCs from the liver in CETP Tg mice virtually abolished hepatic CETP expression and largely reduced plasma CETP concentration, consequently improving the lipoprotein profile. Conversely, augmentation of KCs after Bacille-Calemette-Guérin vaccination largely increased hepatic CETP expression and plasma CETP. Also, lipid-lowering drugs fenofibrate and niacin reduced liver KC content, accompanied by reduced plasma CETP concentration.
  
  
  CONCLUSIONS
  Plasma CETP is predominantly derived from KCs, and plasma CETP level predicts hepatic KC content in humans.
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Sam
authors.initials: S
authors.lastname: van der Tuin
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Nathanja
authors.initials: N
authors.lastname: Tjeerdema
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Andrea D
authors.initials: AD
authors.lastname: van Dam
authors.affiliation: Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Sander S
authors.initials: SS
authors.lastname: Rensen
authors.affiliation: Department of Molecular Genetics, Maastricht University, Maastricht, The Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: Hendrikx
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jimmy F P
authors.initials: JF
authors.lastname: Berbée
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Biljana
authors.initials: B
authors.lastname: Atanasovska
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Fu
authors.affiliation: Department of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden, The Netherlands.
authors.forename: Menno
authors.initials: M
authors.lastname: Hoekstra
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The, Netherlands.
authors.forename: Siroon
authors.initials: S
authors.lastname: Bekkering
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The, Netherlands.
authors.forename: Niels P
authors.initials: NP
authors.lastname: Riksen
authors.affiliation: Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Wim A
authors.initials: WA
authors.lastname: Buurman
authors.affiliation: Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: Greve
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.affiliation: Department of Molecular Genetics, Maastricht University, Maastricht, The Netherlands.
authors.forename: Ronit
authors.initials: R
authors.lastname: Shiri-Sverdlov
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Onno C
authors.initials: OC
authors.lastname: Meijer
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The, Netherlands.
authors.forename: Johannes W A
authors.initials: JW
authors.lastname: Smit
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.|Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.|Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Ko Willems
authors.initials: KW
authors.lastname: van Dijk
authors.affiliation: Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D053480:Cholesterol Ester Transfer Proteins / Q000378:metabolism*; D005260:Female; D006801:Humans; D007728:Kupffer Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged
chemical_list: C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins