Similar to human Familial Hypercholesterolemia, LDL receptor’s function is genetically reduced in WHHL rabbits and they show hypercholesterolemia (FEBS Lett 1980; 118: 81-84; Eur J Biochem 1981; 118: 557-564; Proc Natl Acad Sci USA 1981; 78: 2268-2272; J Biol Chem 1981; 256: 9789-9792). This defect arises from an in-frame deletion of 12 nucleotides that eliminates four amino acids from the cysteine-rich ligand binding domains of the LDL receptor (Science 1986; 232: 1230-1237). From this mutant gene, although the precursor of LDL receptor proteins are synthesized normally, the maturation of the LDL receptor protein is delayed and is not transported to the cell surface at a normal rate (Mol Biol Med 1983; 1: 353-367).

        In our present WHHL rabbits, the average plasma cholesterol levels are about 1,100 mg/dl when they are below 6 month-old, about 900 mg/dl at 12-month-old, and about 800 mg/dl at 18-month-old. The average plasma triglyceride levels are between 150 and 300 mg/dl. About 70% of the cholesterol is distributed in LDL fractions, and only a few % in HDL fractions.

        The rate of accumulation of apoB-100 does not differ in perfusates of liver from normal and WHHL rabbits and little or no apoB-48 is accumulated in VLDL fractions (Proc Natl Acad Sci USA 1983; 80: 6096-6100). Lipoproteins other than VLDL are not secreted from the liver of WHHL rabbits (Proc Natl Acad Sci USA 1983; 80: 6096-6100). An inhibition of the hepatic microsomal triglyceride transfer protein (MTP) activity diminished the VLDL secretion and reduced the plasma LDL levels in homozygous WHHL rabbits. This suggests that MTP inhibitors should have hypolipidemic effects against homozygous familial hypercholesterolemia. (Eur J Pharmacol 2001; 431: 127-131 ).

        The plasma CETP activity of WHHL rabbits is about 2 to 3-fold higher compared with normal rabbits (Arteriosclerosis 1986; 6:345-351). Although the LPL activity of WHHL rabbits is similar to heterozygous WHHL rabbits, the HTGL activity is about 2-fold higher compared with the heterozygotes (Biochem J 1990; 272: 647-651).

        In a kinetic study of ¹²⁵I-labeled chylomicrons, the fractional catabolic rate in WHHL rabbits was similar to normal rabbits (Proc Natl Acad Sci USA 1982; 79: 3623-3627).

        The fractional catabolic rate of HDL apoA-I of WHHL rabbits was about 1.7-fold higher and the synthetic rate was about 50% compared with normal rabbits (Atherosclerosis 1989; 79: 225-230).

        The plasma lipid levels of WHHL rabbits are gradually decreased with age (Metabolism 2000; 49: 552-556). The HMG-CoA reductase activity of the liver microsomal fraction is increased above 12 month-old. The ACAT activity is decreased between 2 month-old and 6 month-old and then remains constant. The activity of cholesterol-7a hydroxylase is almost constant. The cholesterol contents in the whole liver and the microsome fraction are constant. The VLDL secretion rate is decreased with age.

        In our present WHHL rabbits, aortic atherosclerosis is observed grossly from 2 months old despite feeding them a normal standard rabbit chow. The lesions develop first at the orifices of the branches. At 6 month-old, aortic lesions expanded to about 40% of the aortic surface. At 12 month-old, the lesions cover about 70% of the aortic surface. Above 18 month-old, the aortic lesions cover most of the aorta.
        Regarding lesional composition (Arterioscler Thromb 1994; 14: 931-937; J Atheroscler Thromb 1994; 1: 45-52), in early lesions, many macrophages and few SMCs are observed in the intima and some macrophages penetrate into the arterial media.         In transitional lesions observed at about 12 month-old, large foam cells, derived from macrophages, are increased in the deep area of the intima, and a fibromuscular cap covers the surface. Above 18 month-old, cellular components are decreased, but collagen fibers, extracellular lipid accumulation, and cholesterol cleft are increased. In some case, calcium accumulation is also observed in these advanced lesions.

        In our oronary atherosclerosis-prone WHHL rabbits (see the section of "Development of the WHHL rabbit strain"), coronary atherosclerosis is observed from 2 month-old despite feeding them a normal standard rabbit chow. The lesions develop mainly at the main stem of the left coronary artery, the origin of the right coronary artery, and the left circumflex arteries. In rabbits, the left circumflex artery is larger and longer than the left anterior descending artery. The average coronary narrowing (% of plaque area in the area surrounding the internal elastic lamina) of the circumflex artery reaches about 50% at 6 month-old, about 70% at 12 month-old, and about 80% above 18 month-old.
        Lesional composition of coronary plaques is relatively fibromuscular compared with the aortic lesions (Arterioscler Thromb 1994; 14: 931-937). However, several WHHL rabbits show macrophage-rich coronary plaques.
        Atherosclerotic coronary arteries exhibited the enhancement in contraction and Ca²⁺ mobilization in response to serotonin. The 5-HT_1B receptor, which is upregulated by atherosclerosis. most likely mediates the augmenting effects of serotonin. (Circulation 2001; 103: 1289-1295)

        Coronary arteries show compensatory outward remodeling and coronary atherosclerosis-prone WHHL rabbits are useful animal for studies sbout coronary remodeling. We demonstarted the novel insights into coronary lumen preservation during progression of coronary atherosclerosis as follows (Coronary Artery Disease 2004 Nov; 15(7): 419-426);
        Prior quantitative analysis of coronary artery compensatory remodeling is limited by individual variation of arterial size and arterial tapering. Therefore, we developed a new analytical method resolving this limitation and analyzed coronary compensatory remodeling using perfusion-fixed coronary arteries of WHHL rabbits, an animal model for spontaneous coronary atherosclerosis. In the new analysis, we evaluated how lumen area or arterial size was changed with accumulating atherosclerotic plaques compared to before plaque developed. The lumen area modestly decreased below 10% cross-sectional narrowing (CSN), remained constant from 10% to 68% CSN, and diminished sharply despite continued remodeling above 70% CSN. Up to 70% CSN, arterial remodeling progressed quantitatively to maintain constant arterial wall shear stress as well as lumen area. Quantitative analysis eliminating the previous limitation provides the novel insight that coronary compensatory remodeling in atherosclerosis maintains lumen size up to 70% CSN in proportion to wall shear stress.

        Although cerebral atherosclerosis was not observed in WHHL rabbits born before 1995, presently, coronary atherosclerosis-prone WHHL rabbits (see the section of "Development of WHHL rabbit strain") spontaneously suffer from cerebral atherosclerosis without inducing hypertension above 9 month-old (Atherosclerosis 2001; 156 (1): 57-66 ). These lesions are mainly observed in the vertebral arteries, the basilar artery, the confluence of vertebral arteries, and the bifurcation of the basilar artery. However, no lesions were observed in the penetrating arteries. The severity of the lesion is relatively mild and the lesion is fibromuscular. The development of cerebral atherosclerosis is not associated with blood pressure in our WHHL rabbits.

        Atherosclerotic lesions are also observed in the pulmonary artery, carotid arteries, renal arteries, mesenteric artery, celiac artery, and other arteries, while atheromatous lesions are not observed in any small arteries. Regarding lesional composition, although the plaque of the pulmonary artery is macrophage-rich, other arteries have fibromuscular plaques.

In addition, many macrophages/foam cells are observed at the aortic valves.

・	The WHHLMI rabbit is the first rabbit model for spontaneous myocardial infarction．
・	WHHLMI rabbits started to die suddenly from 11 months old without apparent symptoms. Histological analysis revealed that myocardial infarction was observed in 97% of rabbits that died up to 35 months old.
・	The myocardial lesions were widely distributed from the left ventricle, right ventricle, and ventricular septum where coronary arteries showed severe coronary stenosis.
・	Based on the anatomical location, myocardial infarction is classified into subendocardial infarction, intramural infarction, transmural infarction, and subepicardial infarction.
・	In many WHHLMI rabbits, old myocardial infarction was accompanied by fresh myocardial lesions.
・	The aortic and coronary plaques progressed markedly compared to the WHHL rabbits before selective breeding. (Exp Anim 2004; 53 (4): 339-346)
・	In the LCX, 73% of sections showed atheromatous plaques having above 90% lumen area stenosis.
・	The serum cholesterol levels increased by about 200 mg/dl despite there beeing no changes in the triglyceride levels compared tio the WHHL rabbits before selective breeding. (Exp Anim 2004; 53 (4): 339-346)
・	There are no gender difference in aortic and coronary atherosclerosis and the incidence of myocardial lesions, although serum cholesterol levels are high in female. (Exp Anim 2004; 53 (4): 339-346)
・	Relation of the degree of coronary cross sectional narrowing to the onset of myiocardial infarction is more prominent than the relation of serum cholesterol levels. (Exp Anim 2004; 53 (4): 339-346)
・	Many culprit plaques of the LCX are foam cell-rich that produces a marked lumen stenosis or concentric occlusion. The typical plaques were associated with complicated changes, including calcification and intraplaque hemorrhage. In some lesions, the plaque was extremely fragile they had a thin cap beneath which there were accumulating macrophages and lipid cores but few smooth muscle cells.
・	Despite such vulnerable plaques, we were unable to detect the real rupture or thrombus formation in any coronary plaques of WHHLMI rabbits. This suggests that factors other than vulnerable plaque may important to plaque rupture.
・	The electrocardiograms from a WHHLMI rabbit monitored immediately before sudden decease showed the typical change of acute myocardial infarction in humans.
・	WHHLMI rabbits will contribute to studies of regeneration of cardiac muscle by gene therapy.
・	WHHLMI rabbits will be useful to study the mechanisms of plaque stability and plaque rupture or acute coronary syndromes can be produced in WHHLMI rabbits through the introduction of other risk factors.

        Xanthomas are developed at the digital joints and skin of WHHL rabbits. Our WHHL rabbits show hyperinsulinemia but plasma glucose levels are normal under a restriction of feeding.

        Results of crossbreeding of homozygous WHHL rabbits with normal rabbits show that the plasma cholesterol levels of the offsprig are normal. Rabbits with hypercholesterolemia are observed in about half of the offsprig in crossbreeding of homozygous WHHL rabbits with heterozygous WHHL rabbits, and about one-third of offspring in crossbreeding of heterozygous WHHL rabbits with heterozygous WHHL rabbits. In crossbreeding of homozygous WHHL rabbits with homozygous WHHL rabbits, all offspring seffer from hypercholesterolemia. These results indicate that hypercholesterolemia of WHHL rabbits inherits recessively (Bull Azabu Vet Coll 1977; 2: 99-124 (Japanese)). In our preivious experience, the plasma cholestyerol levels were below 300 mg/dl in heterozygous WHHL rabbits and were above 300 mg/dl in the homozgote in a condition of feeding low cholesterol standard chow which contains almost no cholesterol.
        Although the binding activity of the LDL receptor of fibroblasts was normal in heterozygous WHHL rabbits (Eur J Biochem 1981; 118: 557-564), expression of LDL receptor protein is about half of normal in fibroblasts of heterozygous WHHL rabbits (Mol Biol Med 1983; 1: 353-367).

        Every WHHL rabbit does not suffer from coronary atherosclerosis, although the plasma cholesterol levels are similar. Results of selective breeding suggest that development of coronary atherosclerosis is regulated by plural genes (Atherosclerosis 1985; 56: 71-79; Atherosclerosis 1992; 96: 43-52).

      Lipid metabolism of the rabbits resembles humans compared with mice and rats. Regarding lipoproteins secreted from liver, both apoB-48 containing lipoproteins and apoB-100 containing lipoproteins are secreted from the liver of mice and rats, while in humans and rabbits only apoB-100 containing VLDLs are secreted from the liver. In mice and rats, apoB editing enzyme, which stops the synthesis of apoB-100 and produces apoB-48, is expressed not only in the intestine but also in the liver, while in humans and rabbits the apoB editing enzyme is expressed only in the liver. Lipoproteins containing apoB-48 rapidly disappear from the plasma compared with lipoproteins containing apoB-100.
      Regarding the activity of cholesterol ester transfer protein (CETP) in the plasma, CETP plays an important role in the transport of cholesterol ester among lipoproteins in the plasma of humans and rabbits, although this activity is very low in the plasma of mice and rats.
      Regarding hepatic triglyceride lipase (HTGL), this enzyme is bound to the membrane of the hepatic cells in humans and rabbits but not in mice and rats.
      Regarding the response to inhibitors of HMG-CoA reductase, the plasma cholesterol levels are decreased in humans and rabbits but no in mice and rats.

      Therefore, it is suggested that WHHL rabbits are more suitable in research for lipid metabolism than models of mice and rats.

        Mice and rats are resistant to atherosclerosis compared with humans and rabbits.