UBC Theses and Dissertations
Lipoprotein lipase deficiency in a colony of domestic cats Ginzinger, David Gerard
I have investigated the molecular basis of lipoprotein lipase deficiency (LPL) in a colony of domestic cats. Members of this cat colony suffer from chylomicronemia and share many of the same phenotypic features as humans with lipoprotein lipase deficiency. Biochemical analysis revealed that these cats have defective LPL catalytic activity suggesting a molecular defect in the LPL gene. Molecular analysis revealed a point mutation resulting in a substitution of arginine for glycine at amino acid residue 412. Segregation analysis, in vitro mutagenesis and expression studies, all showed that this DNA change is the underlying cause of LPL deficiency in this cat colony. Cats homozygous for this mutation have reduced body mass, growth rates and increased stillbirth rates. Body composition analysis showed a reduction of body fat in the LPL deficient cats. Homozygote cats born to a homozygote queen are more profoundly affected than homozygote cats born to a heterozygote queen. The lack of free fatty acids, as a result of lipoprotein lipase deficiency, may limit the maturation of pre-adipocytes. However, the mechanism by which LPL affects body composition is not certain. LPL deficient cats, have an elevation of serum triglycerides even when maintained on a low fat diet. They also have significant elevations of VLDL-triglycerides, VLDL-cholesterol and decreased LDL-cholesterol. Particle composition analysis indicates that normal cats have a lipid particle composition similar to that of humans with respect to VLDL and LDL. An oral fat tolerance study indicates that homozygotes have a marked reduction in the clearance of plasma triglycerides and heterozygotes have an intermediate clearance rate. To study the role of LPL in atherogenesis, normal cats were fed a cholesterol-enriched diet. The vascular tree and organs were evaluated by experienced pathologists to assess the severity of atherosclerotic disease. Serum lipid measurements and vessel wall lesion assessment were elevated in the cholesterol-fed cats, compared to the cats on a normal diet. The lipid profile was correlated with vessel wall measurements. This study provides the basis for evaluating the susceptibility of the LPL-deficient cats to diet induced atherosclerosis.
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