Lipoprotein lipase (LPL) is an important regulator of lipid and lipoprotein metabolism. It plays a key role in the metabolism of chylomicrons and very low density lipoproteins (VLDL) by hydrolyzing their tryglycerides. Thus, LPL is an important contributor to the process of uptake of fatty acids by the cells. The LPL gene is mostly expressed in adipose tissues and muscles. The protein is then transported from the adipocytes to the plasma membranes of the capillary endothelium, where they are localized by binding to heparan sulfate proteoglycan chains. Apart from adipocytes, gene expression and protein synthesis is also seen in diverse tissues like the PNS, where it is assumed to be involved in myelin synthesis, the central nervous system, where it may play a role in long term potentiation, liver, and heart.
Mutations in the LPL gene leading to a reduction or loss of activity of the enzyme are considered risk factors for hyperlipoproteinemia and atherosclerosis. Homozygous mutations may lead to the more severe familial chylomicronemia syndrome, characterized by a marked increase of chylomicrons and very low levels of HDL-cholesterol in the plasma. Mutations in the LPL gene have also been found to be linked to other diseases such as Alzeimer's, hypertension, and pre-eclampsia.
The LPL gene is located on chromosome 8p22, and spans 30 kb. The gene consists of ten exons, and codes for a 475 amino acid long protein. The protein has a 27 amino acid long signal peptide, and its catalytic centre is formed by three amino acid residues-Ser132, Asp156, and His241.
More than 220 naturally occurring mutations have been found in the LPL gene. The frequency of individual mutations varies according to the population studied. The Ser447Stop mutation has been shown to be present in 20% of the general population. However, this mutation is associated with increased LPL activity. Asn291Ser is the most common mutation found to reduce the LPL activity. In general, allelic heterogeneity is observed in LPL deficiency in different populations. However, a founder effect has been reported in certain populations, such as French Canadians.
Abifadel et al. (2004) identified a novel mutation in the LPL gene in two Lebanese patients, suffering from hyperchylomicronemia with recurrent hepatitis. Both had consanguineous parents, and were later found to be related to each other. PCR of the nine coding exons of the LPL gene, followed by direct sequencing showed homozygosity for the new mutation on exon 5, designated D174V. Fifty normolipedemic controls showed absence of the mutation, which also showed segregation with the disease in the family. The mutation lay in a hydrophobic pocket of the protein in which the catalytic triad is located. Heterozygotes for the mutation were shown to have mildly elevated triglyceride levels without any clinical manifestation. Abifadel et al. (2004) also designed a rapid method to screen this mutation by PCR based site directed mutagenesis, and considered that the finding of this specific mutation causing LPL in Lebanese families could have interesting implications in the diagnosis and screening of familial hyperchylomicronemia.
Foubert et al. (1997) reported two unrelated Moroccan families of Berber ancestry with familial chylomicronemia. In both probands, chylomicronemia manifested in infancy and was complicated with acute pancreatitis at age 2 years. Both probands were homozygous for a Ser259Arg mutation, which results in the absence of LPL catalytic activity both in vivo and in vitro. In heterozygous relatives, a partial decrease in plasma LPL activity was observed, sometimes associated with combined hyperlipidemia. This mutation previously unreported in other populations segregated on an identical haplotype, rarely observed in Caucasians, in both families. Foubert et al. (1997) suggested that LPL deficiency is a cause of familial chylomicronemia in Morocco and may result from a founder effect in patients of Berber ancestry.
Buraiki et al., (1997) screened for two mutations, C to T transition in the codon 207 of the LPL gene and G to A 76 base pairs upstream from the transcription site of apolipoprotein A-1 to identify disease markers among Saudi subjects. The frequencies were 1 per 100 and 1 per 70 for the C-T and G to A mutations, respectively.
Cagatay et al. (2007) performed a meta-analysis using literature searches on the Medline and Embase databases, encompassing the period between 1970 and 2006, on the association of the PvuII polymorphism in the LPL gene with risk of coronary artery disease. A total of 12 studies that included 3289 subjects were selected. These studies investigated the frequency of the PvuII polymorphism and their effects on serum lipids on patients with CAD and healthy controls. Of these, 942 subjects were Saudi Arabians. The results of the meta-analysis revealed no differences in the genotype-frequencies of the PvuII polymorphism between the patients and control subjects. In the CAD and control groups, neither tri-glyceride nor HDL-cholesterol levels were found to differ significantly between the PvuII genotypes by analysis of variance. Thus, PvuII genotypes were not found to affect serum triglyceride or HDL-cholesterol levels significantly.
Al-Jafari et al. (2012) recruited 120 CAD patients and 65 ethnically matched healthy controls to study the association between LPL and CAD in the Saudi population. Three LPL polymorphisms studied were LPL-HindIII, LPL-PvuII and LPL-Ser447Ter. In the case of PvuII, the P+P+ genotype was seen in 41.7% of the CAD group and 38.5% of the control group. For the Ser447Ter genotype, the C/C frequency was 83.3% in the CAD group and 87.7% in the control group. Neither of these polymorphisms showed any significant association with CAD. With regards to the HindIII genotype, the frequency of H+H+ was 50.8% in the CAD group and 44.6% in the control group. The H-H- frequency in the CAD group was 5% and in the control group was 20%. The odds ratio of H+H+ vs H-H- was 4.6 (1.57-13.2) with a p value less than 0.005. Hence, individuals with the H+H+ or H+H- genotype were at a much higher risk of developing CAD compared to individuals with H-H- genotype.
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