Itaru Horiuchi

Effect of ursodeoxycholic acid administration on nucleation time in human gallbladder bile

The object of this study was to determine the effects of ursodeoxycholic acid administration on metastability in human gallbladder bile, as reflected by nucleation time. Bile samples from 10 patients with cholesterol gallstones who underwent preoperative ursodeoxycholic acid treatment exhibited a significantly longer median nucleation time (16 days) than those from 11 patients with cholesterol gallstones who received no preoperative treatment (4 days) (p less than 0.01). On the other hand, the median nucleation times of bile samples from 15 patients with noncholesterol gallstones and 24 patients without gallstones were 15 and 14 days, respectively. In addition, 3 mo of treatment with ursodeoxycholic acid significantly elevated the serum concentration of the antinucleating factor apolipoprotein A-I, from 133.3 +/- 12.3 to 148.6 +/- 13.2 mg/dl (p less than 0.05). These findings suggest that ursodeoxycholic acid retards cholesterol crystal nucleation, thereby inhibiting cholesterol gallstone formation. It is also possible that serum apolipoprotein A-I plays a role in this process.

Effects of pravastatin (CS-514) on biliary lipid metabolism in patients with hyperlipidemia

Pravastatin was administered to 20 patients with hyperlipidemia type IIa and IIb, for a period of 8 to 16 weeks at a daily dose of 10 to 20 mg, to investigate the effects on serum and biliary lipids. At the end of the treatment with pravastatin, the serum cholesterol level was significantly reduced, by 20%, compared with the control level. On the other hand, no significant differences were observed in serum high-density lipoprotein (HDL) cholesterol and triglyceride levels. Additionally, the administration of pravastatin did not change mode % compositions of biliary lipids, such as cholesterol, phospholipids, and total bile acids, as well as individual biliary bile acids. Consequently, there was not any significant change of the cholesterol saturation index. Based on the above results, our findings suggest that, for the treatment of hyperlipidemia, pravastatin is a highly effective cholesterol-lowering drug that does not affect biliary lipid metabolism.

Effect of CS-514, a competitive inhibitor of hydroxymethylglutaryl coenzyme A reductase, on cholesterol gallstone formation in hamsters.

Male golden hamsters fed a glucose diet as a model for cholesterol gallstone formation were used to investigate the effect of CS-514 on the lithogenicity of bile. Treatment with 0.05% (w/w) CS-514 in the diet for 1-4 weeks caused a decrease in plasma cholesterol and triacylglycerol levels. A marked increase in hepatic hydroxymethylglutaryl-CoA reductase activity in vitro and also an increased de novo cholesterol synthesis in the liver were induced by treatment with CS-514 for 1-4 weeks. The concentration of free cholesterol in liver microsomes and the cholesterol 7 alpha-hydroxylase activity were both decreased by treatment with CS-514 for 1 week, but were not affected by treatment for 4 weeks. The cholesterol output into bile and the lithogenic index of bile were double those of the control (glucose diet only) following treatment with CS-514 for 4 weeks, and the subsequent incidence of cholesterol gallstone formation was elevated. The content of free cholesterol and cholesterol ester in the liver was not affected by treatment with CS-514 for 4 weeks. These results suggest that long-term treatment with CS-514 causes a compensatory increase in the synthesis of hydroxymethylglutaryl-CoA reductase which leads to augmented hepatic de novo cholesterol synthesis and subsequent increased cholesterol output followed by an increase in the lithogenicity of bile. CS-514 apparently does not prevent cholesterol gallstone formation in those examples where the mechanism is thought to be due to augmented hepatic de novo cholesterol synthesis (type IV hyperlipidemia).

Analysis of neutral amino acid trasnport systems in the small intestine: A study of brush border membrane vesicles

SummaryTransport of L-proline, L-leucine and L-cysteine was studied in brush border membrane vesicles prepared from guinea pig ileum. Concentrative transport of L-proline, L-leucine and L-cysteine was obtained in the presence of an Na+ gradient from, outside to inside of the vesicles, which indicated contribution of either system A (alanine-preferring) or system ASC (alanine-, serine- and cysteine-preferring) to the transport. When Na+ was replaced by Li+, L-leucine and L-cysteine maintained the same concentrative transport. However, the concentrative transport of L-proline was markedly decreased by Li+-for-Na+ substitution. Strong exchange properties of L-leucine transport via system L (leucine-preferring) was observed with brush border membrane vesicles, in which preloaded L-methionine could be exchanged with labeled L-leucine added outside the vesicles. These results suggest that the small intestine of the guinea pig possesses classical neutral amino acid transport systems such as systems A, ASC and L.

Probucol Promotes Hepatic Uptake of High Density Lipoprotein in Rats

SummaryProbucol significantly reduced high density lipoprotein (HDL)-cholesterol and apolipoprotein AI in rats. Hepatic uptake of radiolabelled human HDL3 increased significantly in vivo and in the isolated perfused rat liver preparation. In vivo, uptake of HDL3 by the adrenal glands also increased significantly. Hepatic cholesterol content in probucol-treated rats tended to increase, whereas newly synthesised cholesterol decreased significantly. The results of the present study suggest that enhanced uptake of HDL is one of the mechanisms of lowering serum HDL with probucol treatment.

Changes in high density lipoproteins in patients with hepatobiliary diseases

SummaryLipids of HDL (high density lipoproteins) and their subfractions (HDL2 and HDL3), and LCAT activity (lecithin: cholesterol acyltransferase) were determined in hepatobiliary diseases without severe hyperbilirubinemia (<10 mg/dl).The decrease in major lipid constituents (cholesterol and phospholipids) of HDL was mainly attributable to the decrease in those of HDL3, except in some liver diseases of acute or severe stage (acute hepatitis in an acute stage and hepatoma) which were accompanied with a simultaneous moderate decrease in those of HDL2 and in fatty liver which showed a preferential decrease in those of HDL2. The LCAT activity also decreased in several diseases. Some of the hepatobiliary diseases, on the contrary, showed an increase in HDL-triglycerides (mostly in HDL3 and in some diseases also in HDL2) which might participate to some extent in secondary hyperlipidemia in the liver parenchymal diseases, although they were the minor lipid constituents of HDL. From results that HDL3 but not HDL2-cholesterol levels significantly correlated with serum total protein, albumin and choline esterase, it was suggested that the decrease in large constituents of HDL, particularly of HDL3, is caused by hepatocellular dysfunction which causes inhibition of protein and lipid syntheses in the liver in most of the hepatobiliary diseases except for fatty liver which has a preferential decrease in HDL2 lipids.