William L. Anthony

Feedback Control of Cholesterol Biosynthesis in the Mouse.

Summary Effects of cholic acid on biosynthesis of hepatic cholesterol and bile acids were studied. Mice maintained on a basal diet, or this diet supplemented with 0.5% cholic acid, received single intraperitoneal injections of mevalonic acid-2-C14 or choles-terol-4-C14. Feces were collected at 24-hour intervals, fecal steroid-C14 was isolated and fractionated, α + β-sterol-C14 and bile acid-C14 were determined. In control mice the distribution of C14 activity in fecal steroids was 60% in the sterol fraction and 40% in the bile acid fraction. This ratio was constant with time after the first 24-hour interval, regardless of the substance injected. It was shown that cholic acid brings about equal decreases in the rates of both hepatic cholesterol and bile acid biosyntheses. Since a preceding study had shown that the rate of bile acid synthesis in mouse liver is inhibited by cholic acid independently of its effect on cholesterol synthesis, it was concluded that the rate of hepatic cholesterol biosynthesis in mice is controlled by cholic acid and its conjugates by means of a double feedback reaction.

Effect of dietary cholic acid on in vivo cholesterol metabolism.

Summary 1. Dietary cholic acid reduced the rate of in vivo hepatic cholesterol synthesis within 3 days, as indicated by incorporated acetate-1-C14. 2. Continued feeding of cholic acid produced no further decrease in hepatic cholesterol synthesis rate over the 21-day period. 3. Increased serum bile acid level correlated with decreased liver cholesterol synthesis rates at all time intervals. 4. There was a small but significant increase in liver cholesterol concentration caused by dietary cholic acid. This increase remained constant throughout the experimental period. 5. Dietary cholic acid had no effect on in vivo kidney and intestine cholesterol synthesis rates.

Effect of Dihydrocholesterol and β-Sitosterol on Cholesterol Atherosclerosis in Rabbits

While dihydrocholesterol lowered total plasma cholesterol in the rabbit, it did not promote the regression of either the aorta lipid fractions or plaque areas in atherosclerotic animals. A comparative study of the toxicities of β-sitosterol and dihydrocholesterol disclosed that dihydrocholesterol, fed for a 7 month period, resulted in aorta plaque formation and caused the development of liver cirrhosis. On the other hand, β-sitosterol produced no toxic effects.

Effects of conjugated bile acids on in vivo cholesterol metabolism in the mouse.

Summary Free and conjugated bile acids had qualitatively similar effects on mouse liver cholesterol levels and in vivo cholesterol-x-C14 synthesis rates. The effects of free bile acids on cholesterol metabolism are not due to the exhaustion of amino acids used in formation of glycine and taurine conjugates.

Effects of Beta-Sitosterol on Regression of Cholesterol Atherosclerosis in Rabbits

Feeding β-sitosterol to atherosclerotic rabbits slightly increased the regression of plasma and liver cholesterol. However, β-sitosterol had no effect on aorta lipid, cholesterol or plaque regression.

Urinary Excretion of Radiosulfur Following Taurine-35S Injection in Zinc Deficient Rats

Summary The effect of zinc deficiency on taurine oxidation was studied by comparing the amounts of labeled-35S found in urinary inorganic sulfate and taurine following injection of taurine-35S into zinc-deficient and zinc-supplemented rats. The results show that rats receiving a diet low in zinc excreted significantly more 35S, more 35SO4 2- and taurine-35S than control animals. These findings suggest zinc deficiency enhanced the rate of taurine oxidation. This conclusion is supported by data showing a significant increase in excretion of 24 hr urinary 14C by zinc-deficient rats over zinc-supplemented control rats following injection of taurine-1,2-14C. The radioactivity in the fecal lipid extract was not affected by zinc deficiency, indicating that zinc-deficient rats were capable of forming taurine-bile acid conjugate.

Effects of β-Sitosterol and Ferric Chloride On Accumulation of Cholesterol in Mouse Liver.∗

Summary 1. Increasing the cholic acid content of a diet rich in cholesterol, significantly increased total liver cholesterol. 2. The addition of β-sitosterol to diets containing cholic acid and cholesterol, decreased total liver cholesterol. 3. Addition of ferric chloride, in varying amounts, to diets rich in cholesterol and cholic acid, resulted in practically no change in total cholesterol content of mouse liver.

Effect of Cholic and Hyodeoxycholic Acids on Metabolism of Exogenous Cholesterol in Mice.

Summary In the female mouse fed a cholesterol-free diet: (1) supplement of 1% cholesterol did not alter liver or carcass cholesterol levels; (2) 1% cholesterol plus 0.5% cholic acid brought about large increases in liver and carcass cholesterol levels; (3) hyodeoxycholic acid reversed the effect of cholic acid and prevented cholesterol accumulation.

Influence of Bile Acids on Cholesterol Metabolism in the Mouse.

Summary Feeding various bile acids to mice for 3 weeks had the following effects: 1. Cholic acid increased hepatic and intestinal cholesterol levels, but had no effect on kidney cholesterol. It decreased hepatic cholesterol synthesis rates, but had no effect on intestinal synthesis rates. 2. Hyodeoxycholic and lithocholic acids decreased liver cholesterol levels. Hyodeoxycholic acid had no effect on intestine and kidney cholesterol, or on intestinal cholesterol-x-C14. Both acids effected large increases in hepatic cholesterol synthesis. 3. Deoxycholic acid significantly decreased liver, small intestine and kidney cholesterol levels. It also decreased hepatic cholesterol synthesis. 4. Results of this study suggest that homeostatic control of cholesterol metabolism in tissues other than liver is independent of hepatic control.

Effect of hyocholic acid on cholesterol and bile acid metabolism in the mouse.

Summary Hyocholic acid effectively prevented accumulation of dietary cholesterol in mice fed diets supplemented with cholesterol but had little or no effect on tissue cholesterol concentrations in mice fed normal diets. Treating mice with antibiotics largely reversed the effect of hyocholic acid, and permitted the accumulation of dietary cholesterol in hyocholic acid-treated mice. It was demonstrated that the hypocholesteremic effect is probably mediated by hyodeoxycholic acid, which arises from the action of intestinal bacteria on hyocholic acid. In animals which received hyocholic or hyodeoxycholic acid, cholic acid disappeared from the bile acid spectrum of the small intestine. Treatment with antibiotics restored cholic acid to the bile acid spectrum of hyocholic acid-treated mice but not to that of hyodeoxycholic acid-treated mice.