Changes in classic and alternative pathways of bile acid synthesis in chronic liver disease.
BACKGROUND
Cholesterol elimination occurs through bile acid synthesis that starts within the liver from 7alpha-hydroxylation or in extrahepatic tissues from 27-hydroxylation. This study was aimed at investigating in vivo these two pathways in patients with chronic liver disease.


METHODS
Serum concentrations of 7alpha- and 27-hydroxycholesterol were measured in 54 patients (29 with primary biliary cirrhosis and 25 with chronic hepatitis C) and 18 controls. The rate of oxysterol plasma appearance was calculated after intravenous infusions of deuterated 7alpha- and 27-hydroxycholesterol in patients (n=8) and control subjects (n=8) who gave consent. The expression of sterol 27-hydroxylase was evaluated in macrophages isolated from 20 subjects.


RESULTS
In patients with liver disease, the rate of plasma appearance of 7alpha-hydroxycholesterol was significantly reduced (1.44+/-0.96 vs. 2.75+/-1.43 mg/hour, p=0.03), the degree of reduction being related with the severity of the disease (p=0.01) whereas that of 27-hydroxycholesterol was unaffected. The rate of plasma appearance of 27-hydroxycholesterol was significantly related to its serum concentrations (r=0.54, p=0.03) and to its release from cultured macrophages ( r=0.85, p=0.03).


CONCLUSIONS
In liver disease 7alpha-hydroxylation of cholesterol seems to be impaired while 27-hydroxylation is unaffected. Serum concentrations of 27-hydroxycholesterol are useful to obtain information on the activity of this alternative pathway.
Crosignani
Andrea
A
Department of Medicine, Surgery and Dentistry, School of Medicine San Paolo, Italy. andrea.crosignani@libero.it
Del Puppo
Marina
M
Longo
Matteo
M
De Fabiani
Emma
E
Caruso
Donatella
D
Zuin
Massimo
M
Podda
Mauro
M
Javitt
Norman B
NB
Kienle
Marzia Galli
MG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001647:Bile Acids and Salts / Q000096:biosynthesis* / Q000378:metabolism; D053898:Biosynthetic Pathways / Q000502:physiology; D016022:Case-Control Studies; D002478:Cells, Cultured; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics / Q000378:metabolism; D005260:Female; D006521:Hepatitis, Chronic / Q000503:physiopathology*; D006801:Humans; D006888:Hydroxycholesterols / Q000097:blood / Q000378:metabolism*; D006900:Hydroxylation; D008105:Liver Cirrhosis, Biliary / Q000503:physiopathology*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008875:Middle Aged
D001647:Bile Acids and Salts; D006888:Hydroxycholesterols; C011724:cholest-5-en-3 beta,7 alpha-diol; C076996:27-hydroxycholesterol; D053493:Cholestanetriol 26-Monooxygenase