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 cholestero l concentrations, hepatic activities and mRNA levels of HMG-CoA reduct ase and cholesterol 7 alpha-hydroxylase and hepatic LDL receptor funct ion and mRNA levels in 23 New Zealand White (NZW) and 17 Watanabe heri table hyperlipidemic (WHHL) rabbits, Plasma cholesterol concentrations were 9.9 times greater in WHHL than NZW rabbits and rose significantl y 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 decl ined > 60% without changing enzyme mRNA levels after cholesterol was f ed, In NZW rabbits, cholesterol feeding inhibited LDL receptor functio n but not mRNA levels, As expected, receptor-mediated LDL binding was reduced in WHHL rabbits, Hepatic cholesterol 7 alpha-hydroxylase activ ity and mRNA levels were 2.8 and 10.4 times greater in NZW than WHHL r abbits, Unexpectedly, cholesterol 7 alpha-hydroxylase activity was red uced 53% and mRNA levels were reduced 79% in NZW rabbits with 2% chole sterol feeding, These results demonstrate that WHHL as compared with N ZW rabbits have markedly elevated plasma and higher liver cholesterol concentrations, less hepatic LDL receptor function, and very low hepat ic cholesterol 7 alpha-hydroxylase activity and mRNA levels, Feeding c holesterol to NZW rabbits increased plasma and hepatic concentrations greatly, inhibited LDL receptor-mediated binding, and unexpectedly sup pressed cholesterol 7 alpha-hydroxylase activity and mRNA to minimum l evels similar to WHHL rabbits, Dietary cholesterol accumulates in the plasma of NZW rabbits, and WHHL rabbits are hypercholesterolemic becau se reduced LDL receptor function is combined with decreased catabolism of cholesterol to bile acids.