Primary dual defect of cholesterol and bile acid metabolism in liver of patients with intrahepatic calculi.
OBJECTIVE
Intrahepatic calculi, which are characterized by cholesterol-rich pigment stones, are highly prevalent in East Asia. Their pathogenesis remains unknown. To elucidate the etiological factors underlying the formation of cholesterol-supersaturated bile, which leads to the formation of cholesterol-rich pigment stones cholesterol and bile acid de novo syntheses in the liver were studied.


METHODS
Liver specimens were assayed for the catalytic activities and steady-state messenger RNA levels of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and cholesterol 7 alpha-hydroxylase.


RESULTS
The activity of HMG-CoA reductase, consistent with the messenger RNA level, was significantly higher in 13 patients with intrahepatic grown pigment stones (11.2 +/- 1.3 pmol.min-1.mg protein-1 [mean +/- SEM; P < 0.0001] for affected hepatic lobes and 13.4 +/- 1.7 [P < 0.0001] for unaffected ones [P < 0.0001]) than in 19 control subjects (6.4 +/- 0.4) and in 29 patients with gallbladder cholesterol stones (2.1 +/- 0.1). On the other hand, the activity of 7 alpha-hydroxylase, consistent with the messenger RNA level, was significantly lower in patients with intrahepatic brown pigment stones (2.8 +/- 0.5 pmol.min-1.mg protein-1 [P < 0.0001] for affected lobes and 2.6 +/- 0.5 [P < 0.0001] for unaffected ones) than in control subjects (6.0 +/- 0.6) and in patients with cholesterol stones (5.1 +/- 0.5).


CONCLUSIONS
In intrahepatic calculi, the formation of supersaturated bile and cholesterol-rich pigment stones may be attributed to the primary dual defect of up-regulated cholesterogenesis and down-regulated bile acid synthesis in the liver.
Shoda
J
J
Department of Gastroenterology, University of Tsukuba, Ibaraki, Japan.
He
B F
BF
Tanaka
N
N
Matsuzaki
Y
Y
Yamamori
S
S
Osuga
T
T
D001483:Base Sequence; D001646:Bile / Q000378:metabolism; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D001653:Bile Ducts, Intrahepatic; D002769:Cholelithiasis / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation
D001647:Bile Acids and Salts; D012333:RNA, Messenger; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase