Gr. Xu et al., UNEXPECTED INHIBITION OF CHOLESTEROL 7-ALPHA-HYDROXYLASE BY CHOLESTEROL IN NEW-ZEALAND WHITE AND WATANABE HERITABLE HYPERLIPIDEMIC RABBITS, The Journal of clinical investigation, 95(4), 1995, pp. 1497-1504
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.