Effects of feeding cholic acid and chenodeoxycholic acid on cholesterol absorption and hepatic secretion

Chenodeoxycholic acid (CDCA), in contrast to cholic acid (CA), reduces cholesterol saturation of bile. The mechanisms for these differences were the object of this study. Investigations were carried out in nine white men; three nonobese subjects and one obese subject were fed a weight-maintenance diet, and five obese patients had a reduced caloric intake for weight reduction. They were given a daily dose of 750-1000 mg CDCA or CA for one month after which they received the other bile acid for another month. The effects of both bile acids on bile acid pool size and hepatic secretion rates of biliary lipids were determined. Total bile acid pools were increased markedly by both CDCA and CA, but to about the same degree for each. Thus, the superior action of CDCA for lowering saturation of bile could not be explained by its effect on the pool sizes of bile acids. On the other hand, hepatic secretion of cholesterol, both during feeding and fasting, was found to be reduced to a greater extent by CDCA than by CA. A theoretical mechanism by which CDCA might lower hepatic outputs of cholesterol is the inhibition of cholesterol absorption. To examine this possibility, cholesterol absorption was estimated by use of an intestinal perfusion technique. No differences were obtained between the two treatment periods for either percentage or net absorption of cholesterol; thus it is unlikely that decreased absorption could account for the reduced cholesterol secretion. Another possibility is that CDCA might affect the interrelations of the three biliary lipids differently than CA. This was explored by measurements of hepatic secretion rates of these lipids. We observed a linear relationship between the secretion rates of bile acids and cholesterol, cholesterol and phospholipids, and bile acids during both treatment periods. However, cholestero1:phospholipid ratios were higher during CA therapy than with CDCA, and they increased still more during fasting in most CA-treated subjects, but not with CDCA. This indicated that there is a marked difference between the two bile acids in the degree of coupling of cholesterol and phospholipids in fasting. We suggest that the reduction in bile saturation on CDCA is most likely the result of changes in the interrelations of the different biliary lipids at the site of their secretion and/or inhibition of cholesterol output from the liver because of suppressed cholesterol synthesis in this organ.Einarsson, K., and S. M. Grundy. Effects of feeding cholic acid and chenodeoxycholic acid on cholesterol absorption and hepatic secretion of biliary lipids in man.J. Lipzd Res. 1980. 21: 23-34. Supplementary key words bile saturation . cholesterol synthesis Oral administration of chenodeoxycholic acid (CDCA) is associated with decreased saturation of bile with cholesterol and may induce dissolution of cholesterol gallstones in man, whereas cholic acid (CA) generally has been ineffective (1 5 ) . Previous studies have shown that the biliary excretion of cholesterol is lower during treatment with CDCA than with CA (6, 7), and this may be an important factor in decreased bile saturation on CDCA. The exact mechanisms by which CDCA lowers the cholesterol secretion have not been clarified. From animal experiments it has been suggested that CDCA is more effective in suppressing the activity of HMG-CoA reductase, the rate determining enzyme in cholesterol synthesis (8). Other studies have shown that bile acids do not directly inhibit HMG-CoA reductase but may indirectly regulate cholesterol synthesis by changing the flow of cholesterol to and/or within the liver (9,lO). Recently Lindblad, Lundholm and Schersten (1 1) demonstrated by acute infusion studies in man that CA and CDCA may have different effects on the secretion of bile cholesterol that are unrelated to changes in HMG-CoA reductase activity and cholesterol synthesis. The present study was undertaken to further elucidate the mechanisms by which CDCA in contrast to CA lowers the secretion rate of bile cholesterol in man. We compared the effects of feeding CDCA and CA on the intestinal absorption of cholesterol, the bile acid pool size, and the hepatic secretion of biliary lipids. The relationships between hepatic outputs of Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; DCA, deoxycholic acid; UDCA, ursodeoxycholic acid: LCA, lithocholic acid; CH, cholesterol; BA, bile acid; PL, phospholipid; HMG, 3-hydroxy-3-n1ethylglutaryl; HMG-CoA reductase, meva1onate:NADP oxidoreductase, EC 1.1.1.34; GLC. gas-liquid chromatography. Journal of Lipid Research Volume 2 1, 1980 23 by gest, on O cber 7, 2017 w w w .j.org D ow nladed fom TABLE 1. Clinical data of subjects (; Ideal Pl'lsma I ' l a r m a Patienta Age Weight \Veight (:holesterol 1'rigl)cerides Clinlcal Hiarol-y V I , kg l l l , ~ M i Ingllll 1 54 78 114 180 I38 2 59 74 95 21 I 215 Adult glucose intolerance 3 5 0 63 93 156 118 4 50 11 1 148 173 186 Hypertension Ischemic heart disease 5 51 124 165 257 20 1 Cholelithiasis 6 61 1 24 17.5 230 207 7 48 95 142 183 158 Ischemic heart disease, Hypertension 8 57 I23 164 2 64 9 I50 57 21 1 264 223 283 Hypertension cholesterol, bile acids, and phospholipids were defined over a wide range of bile acid secretion rates. MATERIALS AND METHODS