title: Increased appearance rate of 27-hydroxycholesterol in vivo in hypercholesterolemia: a possible compensatory mechanism.
abstract: OBJECTIVE
  The first step in the alternative pathway of bile acid biosynthesis is the 27-hydroxylation of cholesterol, which takes place both in liver and extrahepatic tissues. This pathway is believed to play a role in peripheral cholesterol degradation. Aim of this study was to investigate the impact of hyperlipidemia on 27-hydroxycholesterol appearance rate, and to assess the effects induced by treatment with statins.
  
  
  RESULTS
  Seven patients with familial hypercholesterolemia and eight patients with familial combined hyperlipidemia underwent determination of 27-hydroxylation rates in vivo by i.v. infusion of deuterated 27-hydroxycholesterol. Isotope enrichment was assayed by gas chromatography-mass spectrometry, allowing to calculate 27-hydroxycholesterol appearance rates. Six normocholesterolemic subjects were regarded as controls. In some hypercholesterolemic patients the infusions were repeated during treatment with atorvastatin or rosuvastatin. Hydroxylation rates were higher in hypercholesterolemic patients (8.7 ± 2.5 mg/h; controls, 3.4 ± 2.0 mg/h; combined hyperlipidemia, 4.4 ± 1.6 mg/h; mean ± SD, P < 0.01 vs both). After statin treatment, both plasma cholesterol levels and hydroxylation rates dropped by nearly 50%. No difference was detectable between the two statins. A linear correlation was shown between plasma cholesterol and 27-hydroxylation rates.
  
  
  CONCLUSIONS
  Hypercholesterolemia associates with increased 27-hydroxycholesterol appearance rates, which decrease during hypocholesterolemic treatment. The correlation with cholesterol levels supports the view that 27-hydroxylation may act as a compensatory mechanism in a condition of larger plasma cholesterol pool. A regulatory role for hepatic and extrahepatic nuclear receptors seems reasonable. These data prompt novel pharmacological approaches for the management of hypercholesterolemia and the prevention of atherosclerosis.
authors.affiliation: Dipartimento di Medicina, Endocrinologia, Metabolismo e Geriatria, Università degli Studi di Modena e Reggio Emilia, Nuovo Ospedale Civile, via Giardini 1355, 41100 Modena, Italy. marco.bertolotti@unimore.it
authors.forename: M
authors.initials: M
authors.lastname: Bertolotti
authors.forename: M
authors.initials: M
authors.lastname: Del Puppo
authors.forename: F
authors.initials: F
authors.lastname: Corna
authors.forename: C
authors.initials: C
authors.lastname: Anzivino
authors.forename: C
authors.initials: C
authors.lastname: Gabbi
authors.forename: E
authors.initials: E
authors.lastname: Baldelli
authors.forename: L
authors.initials: L
authors.lastname: Carulli
authors.forename: P
authors.initials: P
authors.lastname: Loria
authors.forename: M
authors.initials: M
authors.lastname: Galli Kienle
authors.forename: N
authors.initials: N
authors.lastname: Carulli
mesh_terms: D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D000069059:Atorvastatin; D016022:Case-Control Studies; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D005260:Female; D005464:Fluorobenzenes / Q000627:therapeutic use; D008401:Gas Chromatography-Mass Spectrometry; D006538:Heptanoic Acids / Q000627:therapeutic use; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood*; D006900:Hydroxylation; D006937:Hypercholesterolemia / Q000097:blood* / Q000188:drug therapy* / Q000503:physiopathology; D006950:Hyperlipidemia, Familial Combined / Q000188:drug therapy / Q000503:physiopathology; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000627:therapeutic use
chemical_list: D000924:Anticholesteremic Agents; D005464:Fluorobenzenes; D006538:Heptanoic Acids; D006888:Hydroxycholesterols; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; C076996:27-hydroxycholesterol; D000068718:Rosuvastatin Calcium; D002784:Cholesterol; D000069059:Atorvastatin