Michio Ogura

Role of endogenous and exogenous cholesterol in liver as the precursor for bile acids in rats

There is considerable evidence suggesting that compartmentalized functional pools of cholesterol in the liver contribute differently to the formation of bile acids as the precursor. The present paper deals with the incorporation of [1-14C] acetate and of [1,2-3H] cholesterol carried on lipoproteins (LDL and HDL) into biliary bile acids in perfused rat livers and bile-fistula rats. The results showed that endogenous cholesterol synthesized newly from [1-14C] acetate in the liver was incorporated into both cholic acid and chenodeoxycholic acid in a similar way, while exogenous lipoprotein-[1,2-3H) cholesterol delivered to hepatocytes from hepatic circulation was incorporated into chenodeoxycholic acid at a higher rate.

Increased rate of cholic acid formation from 3α,7α-dihydroxy-5β-cholestane in perfused livers from diabetic rats

Abstract The formation of bile acids from 3α, 7α-dihydroxy-5β-cholestane was comparatively investigated in the perfused livers from normal, streptozotocin-diabetic, and insulin-treated diabetic rats. During the infusion of the sterol substrate, cholic acid accounted for only 11% of the total biliary bile acids in the normal rats, while it increased drastically to 57% in the diabetic rats. This increased proportion of cholic acid tended to be normalized by treatment of the diabetic animals with insulin. These results suggest the possible acceleration of cholic acid formation, involving 12α-hydroxylation of 3α,7α-dihydroxy-5β-cholestane or one of its metabolites in an insulin-deficient state in rats.

Biosynthesis of cholic acid accelerated by diabetes: its mechanism and effect of vanadate administration

[7 beta-3H]3 alpha,7 alpha-Dihydroxy-5 beta-cholestane was infused into the femoral vein of bile-fistula rats. The main metabolites in bile were cholic, chenodeoxycholic, and alpha-muricholic acids. Cholic acid accounted for only 7.5% of the total biliary [3H]bile acids in the normal rats, but 51.8% in the diabetic rats. This increased proportion of cholic acid was partially cancelled by treatment of the diabetic rats with insulin (29.8%) or vanadate (28.8%). These results clearly confirm that an alternative biosynthetic pathway of cholic acid via 3 alpha,7 alpha-dihydroxy-5 beta-cholestane is accelerated by diabetes, and indicate that vanadate has an insulin-like effect on the formation of cholic acid in an insulin-deficient state.

Difference between cholic acid and chenodeoxycholic acid in dependence upon cholesterol of hepatic and plasmatic sources as the precursor in rats

Some difference in functional pool of cholesterol acting as the precursor of bile acids is pointed out between cholic acid and chenodeoxycholic acid. In order to elucidate this problem further, some experiments were performed with rats equilibrated with [7(n)-3H, 4-(14)C] cholesterol by subcutaneous implantation. The bile duct was cannulated in one series of experiments and ligated in another. After the operation 14C-specific radioactivity of serum cholesterol fell, but reached practically a new equilibrium within three days. 14C-Specific radioactivity of serum cholesterol as well as of biliary bile acids in bile-fistula rats and urinary bile acids in bile duct-ligated rats was determined during a three days-period in the new equilibrated state. The results were as follows: (1) 14C-Specific radioactivity of cholic acid and chenodeoxycholic acid in bile was lower than that of serum cholesterol, and 14C-specific radioactivity of cholic acid was clearly lower than that of chenodeoxycholic acid. (2) 14C-Specific radioactivity of cholic acid and beta-muricholic acid in urine was lower than that of serum cholesterol, and 14C-specific radioactivity of cholic acid was lower than that of beta-muricholic acid. (3) Biliary as well as urinary beta-muricholic acid lost tritium label at 7-position entirely during the course of formation from [7(n)-3H, 4-(14)C]cholesterol.

A new simple temperature-controlled membrane oxygenator for the perfusion of isolated rat livers

A new temperature-controlled membrane oxygenator for perfusing isolated rat livers was assembled using a combination of heat-exchangeable rubber tubing and silicon rubber tubing. The apparatus supplied enough oxygen to satisfy the requirements of hemoglobin-free perfused livers.

Effects of cholesterol feeding to maternal rats on metabolism of cholesterol and bile acids in the dams and their offspring

The influence of feeding cholesterol to rats during pregnancy and postpartum (from the 11th day of gestation to the third day after delivery) on the serum and hepatic cholesterol levels and on the bile acid composition in the pool and in the liver in relationship to the dams and their pups was examined. The hepatic content of cholesterol in both dam and offspring increased during cholesterol feeding without any changes in serum cholesterol level. In the dams, mainly the esterified cholesterol was increased; in the pups, mainly the free cholesterol was increased. Cholesterol feeding led to a pronounced increase in the pool of β-muricholic acid and a relative decrease in the lithocholic acid concentration in pregnant rats. In fetal rats, the chenodeoxycholic acid pool was increased by cholesterol intake. The lithocholic acid pool was larger in the postpartum rats fed cholesterol than in the controls, while the concentration of α- and β-muricholic acids was decreased. The neonates of cholesterol-fed dams had a larger pool of chenodeoxycholic acid but a smaller pool of β-muricholic acid. These results suggest that the metabolism of cholesterol and of bile acids in dams and their offspring respond differently to cholesterol intake.