Gizella D. Baker

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 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.

Build-up and regression of inhibitory effects of cholic acid on in vivo liver cholesterol synthesis.

Summary A study of sequence of events during initiation and regression of inhibition of cholesterol synthesis by dietary cholic acid was made in rats. In the initiation study, increases of liver cholesterol and serum bile acid levels paralleled decreases of liver cholesterol-x-C14 activity. There was a decrease in liver phospholipid during the same time interval. In the regression study, serum bile acid and liver cholesterol returned to control levels more rapidly than the rate of liver cholesterol synthesis. The results suggest that dietary cholic acid initially elevates liver cholesterol, which in turn leads to the inhibition of acetate-1-C14 incorporation into liver cholesterol.

EFFECTS OF HYPOPHYSECTOMY, THYROIDECTOMY AND THYROID HORMONES ON STEROID METABOLISM IN THE RAT.

Summary Steroid turnover in normal (N), hypophysectornized (H), I131-thyroidectomized (T), and hypophysectomized-thyroidtreated (HT) rats was investigated. Following injection of dl-mevalonic acid-2-C14, feces were collected for a 14-day period. When compared with normals, cumulative fecal bile acid-C14 excretion was reduced about 20% in H and T; while in HT, bile acid-C14 excretion approached normal rate. Cumulative fecal α + β-sterol-C14 excretion was reduced 28% in T, but was similar to normal in H and HT. Total fecal cholesterol plus coprostanol excretion was reduced in both H (-45%) and T (-25%). Thyroid hormone treatment of hypophysectornized rats resulted in a small increase in fecal sterol excretion, but the daily rate was still below normal (-30%). The total steroid-C14 synthesized from mevalonic acid-2-C14 was reduced from normal in both T and H. HT synthesized almost normal amounts of total steroid-C14. It was concluded that lack of the thyroid hormone in hypophysectomized rats accounts for some of the effects of hypophysectomy on steroid metabolism. However other hormones must also be important, since the effects of thyroidectomy were not the same as those of hypophysectomy and thyroid administration did not restore some aspects of steroid metabolism to normal.

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.

Effect of ferric chloride on mobilization of accumulated liver cholesterol, in mice.

Summary 1. Dietary ferric ions do not increase rate of liver cholesterol mobilization in mice. 2. Mobilization of elevated liver cholesterol is prevented by addition of dietary cholic acid. 3. Evidence is presented which suggests that cholic acid absorption is not prevented by dietary ferric ions.