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Partial ileal bypass surgery in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits resulted in a decrease of low density lipoproteins (LDL)-cholesterol from 14.2 +/- 2.4 to 7.0 +/- 1.2 mmol/l. To investigate the effect of partial ileal bypass on receptor-mediated and receptor-independent LDL catabolism, turnover studies were performed of radiolabeled native LDL and chemically modified LDL (methyl-LDL) in WHHL rabbits after partial ileal bypass, in WHHL control rabbits, and in New Zealand White ("normal") rabbits. The plasma LDL pool in WHHL control rabbits was increased 10-fold. The receptor-mediated LDL clearance was essentially zero in WHHL rabbits, both in controls and after ileal bypass surgery; the fractional catabolic rates for total LDL were equal in both WHHL groups and were also similar to that for methyl-LDL in the normal rabbits. Seventy percent of the total LDL clearance in the normal rabbits occurred via the LDL receptor pathway. In the animals with a partial ileal bypass, the plasma LDL-protein pool was appreciably lower than in WHHL controls (41.6 +/- 5.7 vs 73.4 +/- 9.9 mg/kg, P less than 0.02). The absolute catabolic rate was almost 50% lower in the PIB group (21.4 +/- 2.0 vs 40.0 +/- 7.5 mg X kg-1 X day-1, P less than 0.02). These results indicate that the decrease of LDL after partial ileal bypass surgery in WHHL rabbits is the result of a reduced production rate of LDL.

The effectiveness of partial ileal bypass (PIB) as a counter-measure against atherosclerosis was evaluated in WHHL rabbits. The effects of PIB and sham operation, each performed in five animals, on serum lipids, lipoproteins and plaque formation were investigated. PIB resulted in an immediate and sustained decrease of 52% (range 29-67%) in serum cholesterol, while sham operation had no effect. The main reduction was in LDL cholesterol; VLDL-cholesterol was lowered to a lesser extent. PIB also appeared to change the electrophoretic behaviour of total serum, very low density and low density lipoproteins. Plaque formation, measured 30 weeks after operation in various aortic segments and arteries, was significantly reduced after PIB. It is concluded that an induced lowering of serum cholesterol can prevent atherosclerosis in WHHL rabbits. Also, these animals must be considered as a model for the receptor-defective cellular phenotype of homozygous familial hypercholesterolemia, not for the receptor-negative type, which is the only truly genetically homozygous form.

The effects of bile acid drainage on serum cholesterol levels have been investigated in Watanabe heritable hyperlipidemic rabbits, a unique model for homozygous familial hypercholesterolemia. Cholestyramine medication lowered serum cholesterol concentrations with 38%, while a 33% and a 50% small bowel bypass resulted in a decrease of 56 and 48%, respectively. Cholestyramine treatment after either bypass induced a minor additional fall in serum cholesterol. Ileal bypass and ileal resection were equally effective in reducing serum cholesterol. These results indicate the necessity for further investigation into the potential of bile acid drainage as a therapy in homozygous familial hypercholesterolemia.

Aim of the present study was to compare an alimentary and a hereditary rabbit model for hypercholesterolemia. Serum lipids, serum lipoproteins and distribution and prevention of atherosclerotic plaque formation were studied in (1%) cholesterol-fed NZW rabbits and both heterozygous and homozygous WHHL rabbits. Cholesterol-fed NZW rabbits showed a hypercholesterolemia without hypertriglyceridemia, caused by accumulation of a spectrum of cholesterol ester-rich beta-migrating lipoproteins with a relatively low density. The WHHL rabbits displayed both a hypercholesterolemia with an elevation of LDL, and a hypertriglyceridemia. The hypertriglyceridemia in the WHHL homozygotes was due to accumulation of VLDL remnants and in the heterozygotes to a slight rise in normal pre-beta VLDL. Despite the pronounced quantitative and qualitative differences in lipoproteins, the location and extent of atherosclerotic plaques which had developed after 13 weeks cholesterol-rich diet in NZW rabbits and in 10 months old homozygous WHHL rabbits, was quite similar. Partial ileal bypass surgery lowered serum cholesterol in all three groups and also prevented atherogenesis.