plasma cholesterol levels in NZW rabbits. Hypercholes-The effect of bile acid depletion and replacement with terolemia in WHHL rabbits was related to the combinaglycodeoxycholic acid on plasma cholesterol concentration of dysfunctional LDL receptors and inhibited tions, hepatic low-density lipoprotein (LDL) receptor cholesterol 7a-hydroxylase. Plasma cholesterol concenbinding and messenger RNA (mRNA) levels, and hepatic trations were reduced significantly when cholesterol 7aactivities and mRNA levels for 3-hydroxy-3-methylgluhydroxylase was stimulated even in the absence of LDL taryl coenzyme A (HMG-CoA) reductase and cholesterol receptor function. (HEPATOLOGY 1996;24:882-887.) 7a-hydroxylase was investigated in 19 New Zealand white (NZW) and 15 Watanabe heritable hyperlipidemic (WHHL) rabbits. Bile acid depletion was produced by
It is well established that plasma cholesterol concenexternal bile drainage for 5 days, which maximized chotrations in rabbits are very sensitive to dietary cholesterol lic acid synthesis. Replacement was achieved by infusintake. According to current views, absorbed dietary cholesing glycodeoxycholic acid intraduodenally for 24 hours terol down-regulates both hepatic 3-hydroxy-3-methylgluso that the hepatic bile acid flux reached prefistula levtaryl coenzyme A (HMG-CoA) reductase 4 and the expression els. Plasma and liver cholesterol concentrations were 13 of low-density lipoprotein (LDL) receptors 3 so that feeding times and 50% greater, respectively, hepatic LDL recepcholesterol expands the circulating plasma pool with dietary tor-mediated binding was 26% less, and cholesterol 7acholesterol that is transported mostly by LDL. However, we hydroxylase activity and mRNA levels were 62% and 86%
recently reported that dietary cholesterol also unexpectedly less in WHHL than NZW rabbits. After bile drainage, inhibited cholesterol 7a-hydroxylase, the rate-limiting enplasma cholesterol concentrations decreased 29% in zyme for bile acid synthesis. Because bile acids represent NZW rabbits and 40% in WHHL rabbits and were associthe major product of cholesterol catabolism, reducing their ated with a 2.1-fold increase in hepatic LDL receptorformation can also lead to the accumulation of cholesterol. mediated binding in the NZW rabbits, but there was no Further support for the inverse relationship between bile acid change in the WHHL rabbits. Cholesterol 7a-hydroxysynthesis and plasma cholesterol concentrations comes from lase activity and mRNA levels increased three and four observations in the Watanabe heritable hyperlipidemic times in NZW and WHHL rabbits, respectively, although (WHHL) rabbits. This strain of rabbits shows consistently liver cholesterol levels remained unchanged. Replacehigh plasma cholesterol levels associated with elevated ment with exogenous glycodeoxycholic acid increased plasma concentrations of b-very-low-density lipoprotein choplasma cholesterol concentrations 1.7 times in NZW rablesterol attributed to a deficiency of LDL receptors that is bits and decreased enhanced cholesterol 7a-hydroxylase inherited as a dominant trait. Our recent study in WHHL activity 54%, mRNA levels 86%, cholic acid synthesis 38%, rabbits showed that, in addition to deficient LDL receptor and hepatic LDL receptor-mediated binding 57% in function, cholesterol 7a-hydroxylase activity and messenger NZW rabbits. Bile acid depletion stimulated cholic acid RNA (mRNA) levels were also abnormally low, which contribsynthesis by up-regulating cholesterol 7a-hydroxylase to uted to markedly elevated plasma cholesterol concentrause cholesterol and reduce plasma concentrations subtions. Similar elevations in plasma cholesterol concentrastantially in both NZW and WHHL rabbits, although tions were also observed after cholesterol 7a-hydroxylase was LDL receptors did not function in WHHL rabbits.
inhibited by feeding cholesterol to African green monkeys 8 Glycodeoxycholic acid replacement inhibited elevated and hamsters. 9,10 In contrast, it is well known that rats are cholesterol 7a-hydroxylase, cholic acid synthesis, and resistant to developing hypercholesterolemia when fed chohepatic LDL receptor binding to reestablish baseline lesterol because cholesterol 7a-hydroxylase and bile acid synthesis are stimulated. [11][12][13] Thus, the extra dietary cholesterol is used to make bile acids. Moreover, in specially bred hyper-Abbreviations: HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LDL; low-density cholesterolemia-resistant rabbits, 14 feeding cholesterol did lipoprotein; WHHL, Watanabe heritable hyperlipidemic; mRNA, messenger RNA; NZW, not increase plasma cholesterol concentrations because these New Zealand white.