Hereditary hyperlipidemia in the rabbit due to overproduction of lipoproteins. I. Biochemical studies.

Abstract

An inherited metabolic disorder in a strain of New Zealand White rabbits, characterized by marked hypercholesterolemia (394 ± 1 0 0 mg/dl), with moderately elevated or normal triglyceride levels is described. Low density lipoprotein (LDL), intermediate density lipoprotein (IDL) and very low density lipoprotein (VLDL) cholesterol levels were increased. VLDL and IDL, and to a lesser extent LDL, had increased free cholesterol and esterified cholesterol content, and triglyceride content was reduced. Kinetic studies with 131 I and 125 l-labelled rabbit lipoproteins showed a marked increase in production rates of VLDL apo B and LDL apo B. LDL cholesterol levels were directly related to LDL apo B production rate (r = 0.938, p < 0.001). Both in hypercholesterolemic and normal rabbits injected with labelled VLDL, the specific activity-time curves of VLDL apo B and LDL apo B did not intersect, indicating that LDL apo B was in part derived from sources other than VLDL. No defect was demonstrated in receptormediated catabolism of LDL by cultured skin fibroblasts from hyperlipidemic animals. The fractional catabolic rate of LDL apo B was subnormal, but increased when the expanded LDL apo B pool size was reduced by exchange transfusion; the low fractional catabolism may therefore be attributable, at least in part, to saturation of LDL receptors consequent upon the increased pool size of LDL. The hyperlipidemia in this strain of rabbits may be unique in that the underlying mechanism appears to be overproduction of VLDL and LDL. (Arteriosclerosis 7:105-112, March/April 1987) E xperimental induction of hyperlipidemia with consequent atherosclerosis-like lesions was first documented in cholesterol-fed rabbits more than seventy years ago. 1 This and subsequent dietary studies have provided insights into the pathogenesis of atherosclerosis in humans. More recently two genetic disorders associated with atherosclerosis have been described in laboratory animals. One, in the Watanabe heritable hyperlipidemic (WHHL) rabbit, is associated with pronounced hyperlipidemia in normally fed rabbits 2 and results from a defect in receptor-mediated catabolism of low density lipoprotein (LDL), intermediate density lipoprotein (IDL), and very low density lipoprotein (VLDL). 3 There is secondary overproduction of LDL. 4 ' 5 IDL and LDL levels in plasma are greatly increased. The disorder, which is associated with arterial lesions similar to human atherosclerosis, is in most respects analogous to familial hypercholesterolemia in man. The second disorder is the result of selected inbreeding to produce animals that develop pronounced hyperlipidemia and arterial lesions in response to cholesterol feeding ("hyper-responders"), reflecting a genetic predisposition to the metabolic effects of this diet. 6 Pronounced hypercholesterolemia in a chow-fed New Zealand White rabbit was observed by one of us (ALV). The rabbit was mated with a normal female; four of the first litter of seven were hypercholesterolemic. The disorder has been transmitted vertically t...

Biology and Diseases of Rabbits

“…A brief overview of some of these dietary modifications can be found elsewhere (Jayo et al, 1994). In contrast, the St. Thomas Hospital strain has a normal functioning LDL receptor but still maintains a hypercholesterolemic state (Laville et al, 1987). The WHHL rabbit has a marked deficiency of low-density lipoprotein (LDL) receptors in the liver and other tissues.…”

Biology and Diseases of Rabbits

“…Research efforts into cholesterol metabolism have used the Watanabe heritable hyperlipidemic (WHHL) (Atkinson et al, 1992;Kita et al, 1981) and the St. Thomas Hospital strain rab-bits (LaVille et al, 1987). The WHHL rabbit has a marked deficiency of low-density lipoprotein (LDL) receptors in the liver and other tissues.…”

Influx in vivo of low density, intermediate density, and very low density lipoproteins into aortic intimas of genetically hyperlipidemic rabbits. Roles of plasma concentrations, extent of aortic lesion, and lipoprotein particle size as determinants.

“…The 49 rabbits (Table 1), 32 females and 17 males, weighing 3.3-5.6 kg and aged 9-35 months, were descendants of the founder male of the St. Thomas's Hospital rabbit strain 9 ; the parents of the rabbits were either two hyperlipidemic rabbits or one hyperlipidemic and one normolipidemic rabbit, the latter also being a New Zealand White rabbit. SG 1 pellets (Grain Harvesters Ltd., Wigham, UK) were fed to the rabbits ad libitum.…”