Elevated LDL Triglyceride Concentrations in Subjects Heterozygous for the Hepatic Lipase S267F Variant

Abstract

Abstract-Although naturally occurring loss-of-function mutations in human hepatic lipase (HL) have been described, the biochemical phenotype of heterozygous HL deficiency remains ill defined. This may be due to the relatively small numbers of heterozygous adult carriers of HL mutations in index kindreds. We have identified several new heterozygotes for the catalytically inactive, nonsecreted HL variant S267F in the kindred that was originally ascertained because of hypertriglyceridemia due to the mutant, secreted, circulating apolipoprotein (apo) CII variant apo CII-T. Pairwise comparisons with family controls showed that only the plasma low density lipoprotein triglycerides (LDL TGs) were higher in 11 simple heterozygotes for HL S267F (Pϭ0.002). In contrast, both plasma total TGs and LDL TGs were significantly higher in 12 simple heterozygotes for apo CII-T than in family-matched control subjects (Pϭ0.005 and 0.009, respectively). These findings suggest that the TG content of LDL is increased by heterozygosity for 2 different mutations that affect different proteins involved in lipolysis. However, the mechanisms underlying this compositional change in LDL appear to be different for the 2 mutations, because the total TGs are also elevated in subjects heterozygous for apo CII-T but not in subjects heterozygous for HL S267F. 10 -12 Studies in transgenic rabbits suggest that HL overexpression can result in reduced plasma HDL and IDL and in reduced atherosclerosis. 4 In contrast, disruption of HL in mice can result in increased HDL and, on an APOE-deficient background, increased ␤-migrating VLDL but reduced atherosclerosis. 13 The relevance of such results to human lipoprotein metabolism is unclear.Most patients with HL deficiency due to HL mutations have been ascertained on the basis of dyslipidemia. However, among carriers of HL mutations associated with loss of function, such as R186H, S267F, L334F, and T383M, there are disparities in both the biochemical phenotype and the association with atherosclerosis susceptibility.14 -17 For example, in a Canadian family, compound heterozygotes for HL S267F and T383M had (1) combined hyperlipidemia, (2) TG enrichment of LDL and HDL, (3) ␤-migrating VLDL, (4) impaired chylomicron remnant metabolism, and (5) early coronary heart disease.14 However, the limited number of subjects in this family made it difficult to conclude whether simple heterozygotes had a discrete phenotype. In a Finnish family, compound heterozygotes for L334F and T383M did not have ␤-migrating VLDL but did have TG enrichment of LDL and HDL.15 Also, Finnish heterozygotes for an HL allele that carried R186H and L334F appeared to have TG enrichment of LDL and HDL.16 Homozygosity for a splice-site mutation in HL intron I was associated with hypertriglyceridemia and coronary heart disease; however, there was no obvious biochemical phenotype among heterozygotes. 17The disparity among the results of studies of phenotype in heterozygotes for loss-of-function mutations in HL has many possible explanations. First, ...

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