Plasma lipid secretion and clearance in hyperlipidemic JCR:LA-corpulent rats.

Abstract

The JCR: LA-corpulent rat Is an obese, hyperlipidemic, hyperinsullnemlc strain that Is atherosclerosis-prone and develops myocardlal lesions. The hyperllpldemla Is due to elevated plasma levels of a large relatively triglycerlde-rich very low density lipoprotein (VLDL). Both corpulent and lean male and female rats were studied. Postheparln llpid clearance and apparent hepatic secretion rate after Triton WR1339 Inhibition of lipoproteln llpase were determined. The concentrations of cholesterol and cholesteryl esters were not significantly altered by either treatment TrlglycerIdes showed rapid postheparln clearance In corpulent rats. The apparent hepatic secretion rate was markedly higher In corpulent male rats than In lean male rats, and the rate in corpulent females was again higher, reflecting the higher serum trlglyceride concentrations In corpulent female rats. The relative secretion rate of C 4 8 trlglycerlde molecular species was lower than that of the C: 50 to C: 56 species, while the postheparln clearance of C 4 8 trlglycerlde molecular species was impaired compared to the C: 50 species and those with higher carbon numbers. This effect was more marked In the male than In the female corpulent rats. The results Indicate that VLDL hyperllpldemia In the corpulent rat Is due to hepatic hypersecretlon of VLDL and not to a defect in lipoproteln llpase. Further, the atherogenesls that Is characteristic of the corpulent male rat may be related to the differential metabolism of fatty acids. (Arteriosclerosis 9:869-876, November/December 1989) T he JCR: L A-corpulent rat incorporates the corpulent (cp) gene isolated by Koletsky. 1^ The original strain was derived from a cross of the spontaneously hypertensive (SHR) and Sprague-Dawley rat strains and was hypertensive, hyperlipidemic, and prone to a fulminant atherosclerosis. Hansen 3 incorporated the cp gene into two inbred strains, the SHR/N and the LA/N. Repeated backcrosses (more than 12 times) were made to the parent strains to give two congenic strains. Rats that are homozygous for the cp gene (cp/cp) are obese, while rats that are heterozygous (cp/+) or homozygous normal (+/+) are lean and indistinguishable from the parent strain. The LA/N-cp strain has been described by Elwood et al. 4 and studied as a model for obesity and the effects of high sugar intake. The SHR/N-cp rat is highly sensitive to dietary sucrose and is regarded as a model for the study of obesity and insulin resistance. 5In the course of the development of the LA/N-cp congenic strain, breeding stock from the fifth backcross was used to establish a colony in our laboratories. This colony differs from the fully congenic LA/N-cp and has recently been designated JCR: LA-cp. We have described this strain in previous publications.6 ' 7 The cp/cp male rats spontaneously develop both atherosclerotic and myocarFrom the Departments of Surgery and Pathology, University of Alberta, Edmonton, Alberta, and the Department of Biochemistry, Dalhousie University, Halifax, Nova Scotia, Canada.This work was supp...

Developmental changes in adipose and muscle lipoprotein lipase activity in the atherosclerosis-prone JCR:LA-corpulent rat

“…The contribution of fatty acids from adipose tissue to the liver did not appear to be enhanced in the cp=cp animals in the early development of obesity, since plasma NEFA levels did not increase until week 8. Increased liver lipid production in cp=cp rats is accompanied by hypersecretion of VLDL, 30 a process that may become exacerbated by hepatic insulin resistance and decreased inhibition of VLDL secretion by insulin. 31 Secondly, reduced muscle LPL activity, if not fully compensated by high LPL activity in adipose tissue, may also contribute to hypertriglyceridemia.…”

Rimonabant-mediated changes in intestinal lipid metabolism and improved renal vascular dysfunction in the JCR:LA-cprat model of prediabetic metabolic syndrome

“…Hypertriglyceridemia of the cp/cp rat has been shown to be, at least in part, due to oversecretion of hepatic TG-rich VLDL particles (46,60). Reduction of plasma TG by rimonabant treatment, of over 70%, is striking and greater than that previously reported (23,33).…”

Fibrinolysis and atherogenesis in the JCR:LA-cp rat in relation to insulin and triglyceride concentrations in blood

“…This strain incorporates an autosomal recessive cp (corpulent) gene and JCR:LA-cp rats homozygous for the cp gene (cp/ cp) are obese, insulin resistant, and hypertriglyceridaemic [13]. Heterozygous ( + /cp) and homozygous Diabetologia (1998) Summary Increased concentrations of plasminogen activator inhibitor type-1 (PAI-1) in blood and attenuated fibrinolytic activity, hypertriglyceridaemia, and insulin resistance are common in subjects with obesity and non-insulin-dependent diabetes mellitus who are at markedly increased risk for coronary artery disease.…”

“…In the male cp/cp rat glucose uptake and turnover are no longer responsive to insulin by 12 weeks of age [12]. Marked VLDL hyperlipidaemia is evident and attributable to increased VLDL secretion rather than reduced clearance [13]. The male JCR:LA-cp rat develops atherosclerosis with frank lesions usually beginning after 6 months of age and extensive lesions evident in the aortic arch in 100 % of male cp/cp rats at 9 months of age [14].…”