title: Altered metabolism of low-density lipoprotein and very-low-density lipoprotein remnant in autosomal recessive hypercholesterolemia: results from stable isotope kinetic study in vivo.
abstract: BACKGROUND
  Autosomal recessive hypercholesterolemia (ARH) exhibits different responsiveness to statins compared with that in homozygous familial hypercholesterolemia (FH). However, few data exist regarding lipoprotein metabolism of ARH. Therefore, we aimed to clarify lipoprotein metabolism, especially the remnant lipoprotein fractions of ARH before and after statin therapy.
  
  
  RESULTS
  We performed a lipoprotein kinetic study in an ARH patient and 7 normal control subjects, using stable isotope methodology (10 mg/kg of [(2)H(3)]-leucine). These studies were performed at baseline and after the 20 mg daily dose of atorvastatin. Tracer/tracee ratio of apolipoprotein B (apoB) was determined by gas chromatography/mass spectrometry and fractional catabolic rates (FCR) were determined by multicompartmental modeling, including remnant lipoprotein fractions. FCR of low-density lipoprotein (LDL) apoB of ARH was significantly lower than those of control subjects (0.109 versus 0.450±0.122 1/day). In contrast, the direct removal of very-low-density lipoprotein remnant was significantly greater in ARH than those in control subjects (47.5 versus 2±2%). Interestingly, FCR of LDL apoB in ARH dramatically increased to 0.464 1/day, accompanying reduction of LDL cholesterol levels from 8.63 to 4.22 mmol/L after treatment with atorvastatin of 20 mg/d for 3 months.
  
  
  CONCLUSIONS
  These results demonstrate that ARH exhibits decreased LDL clearance associated with decreased FCR of LDL apoB and increased clearance for very-low-density lipoprotein remnant. We suggest that increased clearance of remnant lipoprotein fractions could contribute to the great responsiveness to statins, providing new insights into the lipoprotein metabolism of ARH and the novel pharmacological target for LDLRAP1.
authors.affiliation: Division of Cardiovascular Medicine, Kanazawa University Graduate School of Medicine, Kanazawa, Japan. ht240z@sa3.so-net.ne.jp
authors.forename: Hayato
authors.initials: H
authors.lastname: Tada
authors.forename: Masa-aki
authors.initials: MA
authors.lastname: Kawashiri
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikewaki
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Terao
authors.forename: Tohru
authors.initials: T
authors.lastname: Noguchi
authors.forename: Chiaki
authors.initials: C
authors.lastname: Nakanishi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuchida
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Takata
authors.forename: Kenji
authors.initials: K
authors.lastname: Miwa
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Konno
authors.forename: Kenshi
authors.initials: K
authors.lastname: Hayashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nohara
authors.forename: Akihiro
authors.initials: A
authors.lastname: Inazu
authors.forename: Junji
authors.initials: J
authors.lastname: Kobayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mabuchi
authors.forename: Masakazu
authors.initials: M
authors.lastname: Yamagishi
mesh_terms: D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D001055:Apolipoproteins B / Q000378:metabolism; D000069059:Atorvastatin; D008401:Gas Chromatography-Mass Spectrometry; D006538:Heptanoic Acids / Q000627:therapeutic use; D006801:Humans; D006937:Hypercholesterolemia / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D007553:Isotope Labeling; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011758:Pyrroles / Q000627:therapeutic use
chemical_list: D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D006538:Heptanoic Acids; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D011758:Pyrroles; D000069059:Atorvastatin