Studies were undertaken to define the role of bile acids in the control of hepatic cholesterogenesis from acetate. Both biliary diversion and biliary obstruction increase the rate of sterol synthesis by the liver 2.5-to 3-fold. After biliary diversion, however, the bile acid content of the liver is decreased, whereas after biliary obstruction, it is markedly increased. Thus, there is no relationship between the tissue content of bile acid and the rate of hepatic cholesterol synthesis. Furthermore, restoration of the enterohepatic circulation of bile acid in animals with biliary diversion fails to prevent the rise in synthetic activity seen after this manipulation. These data indicate that bile acid plays no direct inhibitory role in the regulation of cholesterol synthesis by the liver.Other experiments were therefore undertaken to evaluate the possibility that changes in cholesterogenic activity observed after manipulation of the enterohepatic circulation of bile acid actually are the result of changes in the enterolymphatic circulation of cholesterol. In support of this thesis it was found that intestinal lymphatic diversion causes the same specific enhancement of cholesterol synthetic activity as biliary diversion and that both of these operative procedures increase enzymatic activity at the step mediated by P-hydroxy-P-methyl glutaryl reductase. Furthermore, the increase in the rate of sterol synthesis by the liver seen in animals with biliary diversion can be prevented by the infusion of approximately 7 mg of cholesterol/24 hr in the form of chylomicrons. This is an amount of cho-A portion of this work is presented in abstract form in 1968. Clin. Res. 16: 355. Dr. Dietschy is a Markle Scholar in Academic Medicine.

A B S T R A C T This report describes a "desmosterol suppression" technique with which it has been possible to demonstrate the operation of the cholesterol negative feedback system in the intact animal. 0.1% triparanol in the diet causes a virtually complete block in the conversion of desmosterol to cholesterol by liver and intestine. Since desmosterol is not consumed in the diet, the level of plasma desmosterol can be employed as an index of endogenous sterol production and release into the bloodstream. With this technique it was shown that the feeding of cholesterol for 8 days to rats decreases blood desmosterol levels to less than 5% of control values. Very similar results were obtained when cholesterol synthesis was assayed in vivo with acetate-"C as a cholesterol precursor. These observations indicate that the cholesterol feedback system operates very effectively in the intact animal in suppressing the endogenous contribution to the circulating cholesterol pool. Since intestinal cholesterol synthesis is only slightly inhibited by exogenous cholesterol, these results also indicate that the intestine does not represent a significant source of plasma sterols in the rat.

Abetracf. Groups of rate were prep& with a complete resection of either the jejunum or the ileum. Ratea of cholesterol synthesis in the liver and small bowel, and faecal excretion of neutral and acidic sterols were then measured approximately 63 days after surgery and compared with similar measurements made in control animals that had had transection and reancrstomosis of the intestine. Following resection of the ileum the faecal excretion of neutral sterols (cholesterol + coprostanol) increased from 2.18 to 4.12mg-dar1.100g1. In addition, the taurocholic acid pool decreased from 11.3 to 3.9 mg ~ 100 mg-1 and the half-life for this bile acid declined from 2.8 to 0.4days; hence, the metabolic production rate of taurocholic acid increased from 2.71 to 6.70mg.day-1-100 mg-1. Coincidental with this accentuated turnover of both neutral and acidic sterols, the rate of dc synthesis of cholesterol in the liver and small bowel, as judged by the rate of incorporation of [t-W]acetate into digitonin precipitable sterols, increased to a nearly identical degree in the animale with ilea1 resection. This was accomplished in the liver solely by an increase in the rate of synthesis per unit weight of tissue while in the inteatine there was both increase in the weight of the jejunum and an increase in the rate of cholesterol synthesis per unit weight of tissue. In contrast to these striking changes in sterol balance in animals with ileectomy, the experimental group with jejunectomy did not differ significantly from control animals in rates of hepatio and inhtinaq cholesterol Synthesis or in rates of neutral and acidic sterol excretion. Hence, it is apparent from these studies that following m c t i o n of the ileum in the rat them is increased endogenous synthesis of cholesterol that fully compensates for the augmented excretion of sterols which follows this operation 80 that the circulating serum cholesterol pool remains essentially unchanged.

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