title: Up-regulation of LDL-receptor expression by LDL-immunoapheresis in patients with familial hypercholesterolemia.
abstract: BACKGROUND
  Familial hypercholesterolemia (FH) is characterized by an autosomal dominantly inherited deficiency of LDL-receptor expression on the cell surface, leading to excess plasma LDL-cholesterol and severe premature atherosclerosis. In patients with heterozygous FH, a major therapeutic objective of conventional drug therapy is to stimulate maximally the residual cellular capacity to produce LDL-receptors via inhibition of endogenous cholesterol synthesis. In contrast, LDL-immunoapheresis aims at reducing the plasma LDL-cholesterol level by extracorporeal elimination of LDL particles. The present study investigates whether LDL-immunoapheresis applied in addition to conventional drug therapy is able to further stimulate residual LDL-receptor expression capacity in patients with heterozygous FH via the withdrawal of external cholesterol supply, thereby exerting a second accessory lipid lowering effect.
  
  
  METHODS
  LDL-receptor expression--calculated by transforming mean fluorescence intensities into numbers of antibody binding sites per cell (S/C)--was determined flow-cytometrically on peripheral blood monocytes before and after LDL-apheresis. For a comparison with the maximum obtainable receptor expression capacity, in vitro stimulation experiments under completely LDL deficient conditions were performed.
  
  
  RESULTS
  Prior to LDL-apheresis, LDL-receptor density was comparable in patients (N = 7; 2014 +/- 359 S/C) and controls (N = 10; 1782 +/- 252 S/C). Under in vitro conditions LDL-receptor expression of controls exceeded that of patients with FH by 1.6 times. Immediately after apheresis, LDL-receptor expression significantly increased to almost the same level as obtained by in vitro stimulation (3640 +/- 423 S/C and 3632 +/- 572 S/C). The LDL-receptor expression in FH subsequent to LDL-apheresis exhibited two patterns of kinetics [Type 1: maximal receptor stimulation (288 +/- 70%; P < 0.07) already during apheresis; Type 2: highest receptor density 24 hours after treatment (149 +/- 11%; P < 0.01)].
  
  
  CONCLUSIONS
  These results demonstrate that despite drug therapy, LDL-apheresis significantly stimulates the residual LDL-receptor expression in FH via the reduction of available extracellular cholesterol resulting in delayed reappearance of hypercholesterolemia in between treatments.
authors.affiliation: Department of Nephrology, University of Vienna, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Streicher
authors.forename: P
authors.initials: P
authors.lastname: Valent
authors.forename: H
authors.initials: H
authors.lastname: Schmidt
authors.forename: G
authors.initials: G
authors.lastname: Sengölge
authors.forename: O
authors.initials: O
authors.lastname: Wagner
authors.forename: W
authors.initials: W
authors.lastname: Strobl
authors.forename: W H
authors.initials: WH
authors.lastname: Hörl
authors.forename: K
authors.initials: K
authors.lastname: Derfler
mesh_terms: D000328:Adult; D001666:Binding Sites, Antibody; D001781:Blood Component Removal / Q000379:methods*; D002478:Cells, Cultured; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000378:metabolism* / Q000628:therapy; D007163:Immunosorbent Techniques; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011973:Receptors, LDL / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D008078:Cholesterol, LDL; D011973:Receptors, LDL