Maternal expression of functional lipoprotein lipase and effects on body fat mass and body condition scores of mature cats with lipoprotein lipase deficiency.

OBJECTIVE: To assess effects of deficiency of lipoprotein lipase (LPL) on body condition scores and lean and fat body masses of adult cats. ANIMALS: 12 cats without LPL mutations and 23 cats that were heterozygous or homozygous carriers of the Gly412Arg LPL mutation. PROCEDURE: Lean and fat body masses were estimated by use of body condition scores and change in enrichment of serum after IV administration of deuterium oxide. Mass spectroscopy and infrared absorbance methods were used to determine deuterium enrichment. RESULTS: Fat body mass (mean +/- SD; 0.2 +/- 0.1 kg) and percentage body fat (6.2 +/- 1.4%) of homozygotes were significantly less than those of clinically normal cats and heterozygotes (0.7 +/- 0.1 kg, 18.2 +/- 1.6% and 0.5 +/- 0.1 kg, 15.6 +/- 1.7%, respectively). Homozygous offspring of homozygous dams had significantly less fat body mass (0.1 +/- 0.1 kg) and percentage body fat (2.1 +/- 1.0%) than homozygous offspring of heterozygous dams (0.3 +/- 0.1 kg and 9.2 +/- 1.7%, respectively). Lean body mass did not differ significantly among groups. For all groups, percentage body fat was significantly correlated with body condition score (r= 0.65), and body condition scores supported findings for fat body mass. CONCLUSIONS AND CLINICAL RELEVANCE: Deficiency of LPL activity in cats diminishes stores of body fat. This is consistent with a low rate of de novo synthesis of fat. The effect of dam on body masses in mature LPL-deficient cats indicates nutrient programming of adipose formation during gestation or lactation.

Phenotypic correction of feline lipoprotein lipase deficiency by adenoviral gene transfer.

Previous studies have revealed that adenovirus-mediated ectopic liver expression of human LPL (huLPL) can efficiently mediate plasma triacylglycerol (TG) catabolism in mice despite its native expression in adipose and muscle tissue. We aimed to explore the feasibility of liver-directed gene transfer and enzyme replacement for human LPL deficiency in a larger, naturally occurring feline animal model of complete LPL deficiency that is remarkably similar in phenotype to the human disorder. A cohort of LPL-deficient (LPL -/-) cats was given an intravenous injection of 8 x 10(9) PFU/kg of a CMV promoter/enhancer-driven, E1/E3-deleted adenoviral (Ad) vector containing a 1.36-kb huLPL cDNA (Ad-LPL) or reporter alkaline phosphatase gene (Ad-AP). After Ad-LPL administration, active, heparin-releasable huLPL was readily detected along with a 10-fold reduction in plasma TGs, disappearance of plasma TG-rich lipoproteins up to day 14, and enhanced clearance of an excess intravenous fat load on day 9. However, antibody against the huLPL protein was detected on day 14 in cats receiving Ad-LPL and adenovirus-specific neutralizing antibody was present 7 days after gene transfer in both cat cohorts. Tissue-specific expression of the huLPL transgene relative to controls was confirmed by RT-PCR. While huLPL expression was evident in the liver, other tissues including spleen and lung expressed huLPL message, in direct correlation with histological evidence of increased Oil red O (ORO)-positive neutral lipid influx. In contrast, intravenous LPL enzyme replacement therapy (ERT) led to rapid disappearance of 9000 mU/kg of active bovine LPL enzyme from the circulation, with t1/2 occurring at <10 min in two LPL-/- cats. Heparin injection 1 hr later released <10% of the original bovine LPL, further indicating its rapid systemic clearance, inactivation, or degradation as well as its ineffectiveness as a viable therapeutic alternative for complete LPL deficiency. Although LPL gene transfer and expression via this first-generation Ad vector was limited by the immune response against both the human LPL protein and adenovirus our results clearly provide a key advance supporting further development of LPL gene therapy as a viable therapeutic option for clinical LPL deficiency.

Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.

Genes have a major role in the control of high-density lipoprotein (HDL) cholesterol (HDL-C) levels. Here we have identified two Tangier disease (TD) families, confirmed 9q31 linkage and refined the disease locus to a limited genomic region containing the gene encoding the ATP-binding cassette transporter (ABC1). Familial HDL deficiency (FHA) is a more frequent cause of low HDL levels. On the basis of independent linkage and meiotic recombinants, we localized the FHA locus to the same genomic region as the TD locus. Mutations in ABC1 were detected in both TD and FHA, indicating that TD and FHA are allelic. This indicates that the protein encoded by ABC1 is a key gatekeeper influencing intracellular cholesterol transport, hence we have named it cholesterol efflux regulatory protein (CERP).