Simultaneous determination of plasma mevalonate and 7alpha-hydroxy-4-cholesten-3-one levels in hyperlipoproteinemia: convenient indices for estimating hepatic defects of cholesterol and bile acid syntheses and biliary cholesterol supersaturation.
The high prevalence of cholesterol gallstone disease in hypertriglyceridemic patients may be associated with frequent metabolic defects in cholesterol and bile acid syntheses and in the concomitant formation of bile supersaturated with cholesterol. This study had the two aims: 1) to assess whether the defects as well as the degree of biliary cholesterol supersaturation in patients with hyperlipoproteinemia (HLP) can be estimated by the simultaneous determination of plasma mevalonate (MVL) and 7alpha-hydroxy-4-cholesten-3-one (C4); and 2) to assess the possible application of an estimated cholesterol saturation index ([CSI]E) as a means of evaluating the clinical effects of simvastatin on biliary lipid composition. Biliary cholesterol supersaturation was observed in patients with both IIa and IV HLP types. Consistent with the high activity and steady-state messenger RNA level of 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase, plasma MVL was significantly higher in 86 patients with HLP (38 type IIa, 44.1 +/- 2.4 nmol/L and 48 type IV, 56.7 +/- 2.3; P < .01) than in 41 normolipidemic subjects (34.2 +/- 1.5), closely correlating with the molar percentage of cholesterol in bile (r = .61, P = .0001; n = 86). On the other hand, consistent with the high activity and messenger RNA level of cholesterol 7alpha-hydroxylase, plasma C4 was significantly higher in patients with HLP (type IIa, 28.8 +/- 2.3 nmol/L and type IV, 38.3 +/- 2.7; P < .01) than in normolipidemic subjects (17.4 +/- 1.5). Plasma C4 was closely correlated with plasma MVL (r = .40, P = .0001; n = 86), but was inversely correlated with the molar percentage of bile acids in bile (r = .49, P = .0001; n = 86). Assuming that cholesterol supersaturation in patients with HLP may be governed by both an enhanced cholesterol secretion (closely reflected by plasma MVL) and a decreased secretion of bile acids (closely reflected by plasma C4), the multivariate linear regression-analyses revealed that an index defined as estimated CSI ([CSI]E) (%) in patients with HLP was given by the following equation using plasma MVL and C4 (nmol/L): [CSI]E = 1[MVL] + 0.7[C4] + 44.4. Biliary cholesterol supersaturation in patients treated with simvastatin improved in a manner parallel to the time course of decreases in plasma MVL and C4. The [CSI]E before and at the end of treatment were correlated with biliary CSI. These results indicate that defects of hepatic cholesterogenesis, and bile acid synthesis, and the degree of biliary cholesterol supersaturation in patients with HLP can be estimated exactly by the simultaneous determination of plasma MVL and C4; furthermore [CSI]E may be adopted for clinical use as a convenient index of biliary CSI.
Shoda
J
J
Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.
Miyamoto
J
J
Kano
M
M
Ikegami
T
T
Matsuzaki
Y
Y
Tanaka
N
N
Osuga
T
T
Miyazaki
H
H
D000328:Adult; D000368:Aged; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002783:Cholestenones / Q000097:blood*; D002784:Cholesterol / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D006951:Hyperlipoproteinemias / Q000097:blood*; D007408:Intestinal Absorption; D008099:Liver / Q000378:metabolism*; D008148:Lovastatin / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008798:Mevalonic Acid / Q000097:blood*; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D019821:Simvastatin
D001647:Bile Acids and Salts; D002783:Cholestenones; D012333:RNA, Messenger; C002656:7 alpha-hydroxy-4-cholesten-3-one; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase; D008798:Mevalonic Acid