Abstract
Lipoprotein lipase (LPL) is a key rate-limiting enzyme for the hydrolysis of triacylglycerol (TAG) in chylomicrons and very low-density lipoprotein. Given that postprandial assessment of lipoprotein metabolism may provide a more physiological perspective of disturbances in lipoprotein homeostasis compared to assessment in the fasting state, we have investigated the influence of two commonly studied LPL polymorphisms (rs320, HindIII; rs328, S447X) on postprandial lipaemia, in 261 participants using a standard sequential meal challenge. S447 homozygotes had lower fasting HDL-C (p = 0.015) and a trend for higher fasting TAG (p = 0.057) concentrations relative to the 447X allele carriers. In the postprandial state, there was an association of the S447X polymorphism with postprandial TAG and glucose, where S447 homozygotes had 12% higher TAG area under the curve (AUC) (p = 0.037), 8.4% higher glucose-AUC (p = 0.006) and 22% higher glucose-incremental area under the curve (IAUC) (p = 0.042). A significant gene–gender interaction was observed for fasting TAG (p = 0.004), TAG-AUC (Pinteraction = 0.004) and TAG-IAUC (Pinteraction = 0.016), where associations were only evident in men. In conclusion, our study provides novel findings of an effect of LPL S447X polymorphism on the postprandial glucose and gender-specific impact of the polymorphism on fasting and postprandial TAG concentrations in response to sequential meal challenge in healthy participants.
Highlights
Large prospective cohort studies have identified elevated non-fasting triacylglycerol (TAG) concentrations as an independent risk factor for cardiovascular disease (CVD) [1]
The frequency of carriers of 447X in this study was consistent with published reports in Caucasian population [19]. 56% of participants were homozygous for the H1 major allele for HindIII (n = 131) with 43% H2 minor allele carriers (n = 100)
Values are meanstandard deviation. p-Values are from a linear model testing the association with Lipoprotein lipase (LPL)-S447X, adjusted for age, gender, body mass index (BMI); Abbreviations: TC, total cholesterol; TAG, triacylglycerol; high-density lipoprotein cholesterol (HDL-C), high density lipoprotein cholesterol; low-density lipoprotein cholesterol (LDL-C), low density lipoprotein cholesterol; Non-esterified fatty acids (NEFA), non-esterified fatty acids; homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment—insulin resistance; For the baseline analysis, the insulin and HOMA-IR values were available for 166 participants; For the postprandial analysis, the insulin area under the curve (AUC) and incremental area under the curve (IAUC) data was available for 79 participants
Summary
Large prospective cohort studies have identified elevated non-fasting triacylglycerol (TAG) concentrations as an independent risk factor for cardiovascular disease (CVD) [1]. Endothelial associated Lipoprotein lipase (LPL) (E.C. 3.1.1.34) plays an important role in the metabolism and clearance of triacylglycerol (TAG)-rich lipoproteins from the circulation [5] and atherogenesis, where it influences the interaction between atherogenic lipoproteins and receptors on the vascular wall [6] Enzymes such as Lipoprotein lipase (LPL) (E.C. 3.1.1.34) that regulate lipoprotein metabolism in the postprandial state [7] are of interest to the prevention of CVDs. Several polymorphisms in the LPL gene have been shown to lead to a reduction in enzyme synthesis and activity and, to date, rs320 [HindIII (G/T)] and rs328 [Serine 447 Stop S447X (C/G)] have been the most extensively studied. In the present study, we investigated the association of the two commonly studied LPL polymorphisms [rs320 (HindIII) and rs328 (S447)] with fasting and postprandial lipid concentrations by using a standard sequential meal challenge and examined the penetrance of genotype according to gender, with gender previously shown to be a modulator of the impact of other variants on postprandial TAG handling [18]
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