The expression of type III hyperlipoproteinemia: involvement of lipolysis genes

Abstract

Type III hyperlipoproteinemia (HLP) is mainly found in homozygous apolipoprotein (APO) E2 (R158C) carriers. Genetic factors contributing to the expression of type III HLP were investigated in 113 hyper-and 52 normolipidemic E2/2 subjects, by testing for polymorphisms in APOC3, APOA5, HL (hepatic lipase) and LPL (lipoprotein lipase) genes. In addition, 188 normolipidemic Dutch control panels (NDCP) and 141 hypertriglyceridemic (HTG) patients were genotyped as well. No associations were found for four HL gene polymorphisms and two LPL gene polymorphisms and type III HLP. The frequency of the rare allele of APOC3 3238 G4C and APOA5 À1131 T4C (in linkage disequilibrium) was significantly higher in type III HLP patients when compared with normolipidemic E2/2 subjects, 15.6 vs 6.9% and 15.1 vs 5.8%, respectively, (Po0.05). Furthermore, the frequencies of the APOA5 c.56 G4C polymorphism and LPL c.27 G4A mutation were higher in type III HLP patients, though not significant. Some 58% of the type III HLP patients carried either the APOA5 À1131 T4C, c.56 G4C and/or LPL c.27 G4A mutation as compared to 27% of the normolipidemic APOE2/2 subjects (odds ratio 3.7, 95% confidence interval ¼ 1.8 -7.5, Po0.0001). The HTG patients showed similar allele frequencies of the APOA5, APOC3 and LPL polymorphisms, whereas the NDCP showed similar allele frequencies as the normolipidemic APOE2/2. Patients with the APOC3 3238 G4C/APOA5 À1131 T4C polymorphism showed a more severe hyperlipidemia than patients without this polymorphism. Polymorphisms in lipolysis genes associate with the expression and severity of type III HLP in APOE2/2.

Effect of apolipoprotein E genotype on apolipoprotein B-100 metabolism in normolipidemic and hyperlipidemic subjects

“…Furthermore, there may be reduced competition for LDL receptor-mediated removal of VLDL remnants, which is apoE-dependent ( 32 ). Our observation supports the notion that apoE2 homozygosity contributes to altered lipoprotein metabolism but is not suffi cient to cause the development of type III hyperlipidemia ( 6,32 ), and that additional genetic polymorphisms ( 39,40 ), such as polymorphisms in proteins that regulate lipolysis of lipoproteins ( 34 ) and/or other environmental factors leading to insulin resistance and obesity ( 41 ), contribute to the expression and severity of type III hyperlipidemia.…”

“…Collectively, these kinetic defects may account for the dyslipoproteinemia seen in our apoE2/E2 type III hyperlipidemic subjects. Whether downregulation of VLDL receptors or other extrahepatic receptors ( 31,32 ), or the inhibition of lipolytic enzymes by other apoproteins, such as apoC-III ( 33,34 ), contributes further to the impaired catabolism and accumulation of ␤ -VLDL particles in circulation requires further investigation.…”

Hypertriglyceridemia

“…Remainder of the clinical syndromes Table 8.2 is poorly characterized and may not be distinguishable from acquired causes of hypertriglyceridemia except for the presence of a strong family history. For example, in familial disorder of type III hyperlipoproteinemia or dysbetalipoproteinemia, the patients usually are homozygous for apolipoprotein E2; but its manifestation requires an additional trigger such as diabetes, obesity, hypothyroidism, or renal disease [14][15][16]. Clinically, these patients present with tuberoeruptive xanthomas and xanthomas in palm creases (xanthoma palmaris striata), and with features of coronary and peripheral arterial disease [17].…”

Unraveling hyperlipidemia type III (dysbetalipoproteinemia), slowly

“…1 Only very few lipid disorders seem to be more complex and poorly understood than the type III HLP by Fredrickson (or so-called dysbetalipoproteinemia). This is true despite the fact that type III HLP had been described in great detail more than 33 years ago 2 and since then had been studied intensively by the most dedicated, leading lipid researchers worldwide.…”

“…This extremely challenging project has now been undertaken by Peter Henneman and his colleagues with their paper entitled 'The expression of type III hyperlipoproteinemia: involvement of lipolysis genes'. 1 Henneman et al 1 studied for known genetic variants of various lipolysis genes and their contribution to the expression of type III HLP in a total of 165 apo E 2/2 patients. Of these patients, 113 were hyperlipidemic and 52 were normolipidemic.…”