Unexpected inhibition of cholesterol 7 alpha-hydroxylase by cholesterol in New Zealand white and Watanabe heritable hyperlipidemic rabbits.

We investigated the effect of cholesterol feeding on plasma cholesterol concentrations, hepatic activities and mRNA levels of HMG-CoA reductase and cholesterol 7 alpha-hydroxylase and hepatic LDL receptor function and mRNA levels in 23 New Zealand White (NZW) and 17 Watanabe heritable hyperlipidemic (WHHL) rabbits. Plasma cholesterol concentrations were 9.9 times greater in WHHL than NZW rabbits and rose significantly in both groups when cholesterol was fed. Baseline liver cholesterol levels were 50% higher but rose only 26% in WHHL as compared with 3.6-fold increase with the cholesterol diet in NZW rabbits. In both rabbit groups, hepatic total HMG-CoA reductase activity was similar and declined > 60% without changing enzyme mRNA levels after cholesterol was fed. In NZW rabbits, cholesterol feeding inhibited LDL receptor function but not mRNA levels. As expected, receptor-mediated LDL binding was reduced in WHHL rabbits. Hepatic cholesterol 7 alpha-hydroxylase activity and mRNA levels were 2.8 and 10.4 times greater in NZW than WHHL rabbits. Unexpectedly, cholesterol 7 alpha-hydroxylase activity was reduced 53% and mRNA levels were reduced 79% in NZW rabbits with 2% cholesterol feeding. These results demonstrate that WHHL as compared with NZW rabbits have markedly elevated plasma and higher liver cholesterol concentrations, less hepatic LDL receptor function, and very low hepatic cholesterol 7 alpha-hydroxylase activity and mRNA levels. Feeding cholesterol to NZW rabbits increased plasma and hepatic concentrations greatly, inhibited LDL receptor-mediated binding, and unexpectedly suppressed cholesterol 7 alpha-hydroxylase activity and mRNA to minimum levels similar to WHHL rabbits. Dietary cholesterol accumulates in the plasma of NZW rabbits, and WHHL rabbits are hypercholesterolemic because reduced LDL receptor function is combined with decreased catabolism of cholesterol to bile acids.

[1]  M. Pape,et al.  ACAT inhibition decreases LDL cholesterol in rabbits fed a cholesterol-free diet. Marked changes in LDL cholesterol without changes in LDL receptor mRNA abundance. , 1994, Arteriosclerosis and thrombosis : a journal of vascular biology.

[2]  G. Ness,et al.  Different feedback regulation of hepatic cholesterol and bile acid synthesis by glycodeoxycholic acid in rabbits. , 1993, Gastroenterology.

[3]  S. Smith,et al.  Bile acid excretion and cholesterol 7 alpha-hydroxylase expression in hypercholesterolemia-resistant rabbits. , 1993, Journal of lipid research.

[4]  J. Horton,et al.  Dietary fatty acids regulate hepatic low density lipoprotein (LDL) transport by altering LDL receptor protein and mRNA levels. , 1993, The Journal of clinical investigation.

[5]  G. Ness,et al.  Differing effects of cholesterol and taurocholate on steady state hepatic HMG-CoA reductase and cholesterol 7 alpha-hydroxylase activities and mRNA levels in the rat. , 1992, Journal of lipid research.

[6]  J. Cuthbert,et al.  Regulation of hepatic sterol metabolism in the rat. Parallel regulation of activity and mRNA for 7 alpha-hydroxylase but not 3-hydroxy-3-methylglutaryl-coenzyme A reductase or low density lipoprotein receptor. , 1992, The Journal of biological chemistry.

[7]  T. Parker,et al.  Control of variance in experimental studies of hyperlipidemia using the WHHL rabbit. , 1991, Journal of lipid research.

[8]  P. Hylemon,et al.  Regulation of cholesterol 7 alpha-hydroxylase mRNA and transcriptional activity by taurocholate and cholesterol in the chronic biliary diverted rat. , 1991, The Journal of biological chemistry.

[9]  M. Poznansky,et al.  Cholesterol-mediated regulation of HMG-CoA reductase in microsomes from human skin fibroblasts and rat liver. , 1990, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[10]  M. Brown,et al.  Progress in understanding the LDL receptor and HMG-CoA reductase, two membrane proteins that regulate the plasma cholesterol. , 1984, Journal of lipid research.

[11]  M. Brown,et al.  Cholesterol synthesis in vivo and in vitro in the WHHL rabbit, an animal with defective low density lipoprotein receptors. , 1983, Journal of lipid research.

[12]  J. Dietschy,et al.  Sterol synthesis in vivo in 18 tissues of the squirrel monkey, guinea pig, rabbit, hamster, and rat. , 1983, Journal of lipid research.

[13]  J. Dietschy,et al.  Correlation of low and high density lipoprotein binding in vivo with rates of lipoprotein degradation in the rat. A comparison of lipoproteins of rat and human origin. , 1982, The Journal of biological chemistry.

[14]  M. Brown,et al.  Saturation and suppression of hepatic lipoprotein receptors: a mechanism for the hypercholesterolemia of cholesterol-fed rabbits. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[15]  Y. Watanabe.  Serial inbreeding of rabbits with hereditary hyperlipidemia (WHHL-rabbit). , 1980, Atherosclerosis.

[16]  D. B. Zilversmit,et al.  Chylomicron remnant cholesteryl esters as the major constituent of very low density lipoproteins in plasma of cholesterol-fed rabbits. , 1977, Journal of lipid research.

[17]  Y. Watanabe,et al.  A heritable hyperlipemic rabbit. , 1975, Jikken dobutsu. Experimental animals.

[18]  Oliver H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[19]  M. Katan,et al.  Hypo- and hyperresponders: individual differences in the response of serum cholesterol to changes in diet. , 1987 .

[20]  M. Brown,et al.  Receptor-mediated endocytosis of low-density lipoprotein in cultured cells. , 1983, Methods in enzymology.

[21]  K. Hellstroem,et al.  ON THE BILE ACID AND NEUTRAL FECAL STEROID EXCRETION IN MAN AND RABBITS FOLLOWING CHOLESTEROL FEEDING. BILE ACIDS AND STEROIDS 150. , 1965, Acta physiologica Scandinavica.