Expression of type III hyperlipoproteinemia in patients homozygous for apolipoprotein E-2 is modulated by lipoprotein lipase and postprandial hyperinsulinemia

Abstract

Type III hyperlipoproteinemia (HLP) is a multifactorial disorder associated with homozygosity for the apolipoprotein (apo) E-2 allele. Factors which may promote the development of HLP include lipoprotein lipase (LPL) and hyperinsulinemia. These factors were investigated in eight patients with type III HLP and in nine normolipidemic controls. In vitro the interaction of apoE with LPL was analyzed in cell binding assays. All type III HLP patients showed delayed triglyceride (TG) clearance and remnant lipoprotein accumulation in an oral fat tolerance test. Normolipidemic apoE-2/2 controls revealed normal TG clearance comparable to apoE3/3 controls. HLP patients showed lower LPL activity and mass than controls. Analysis of the LPL gene revealed an Asn 291-->Ser mutation in three patients and a -93 T-G substitution combined with an Asp 9-->Asn mutation in one control subject. In addition to LPL abnormalities, postprandial hyperinsulinemia was observed in five out of eight patients. In vitro LPL compensated the defective function of apoE-2 in mediating remnant lipoprotein binding to cells. In summary, seven out of eight patients with type III HLP showed LPL abnormalities and/or postprandial hyperinsulinemia. Together with the in vitro data these findings support a coordinate effect of apoE and LPL for the manifestation of type III HLP. Hyperinsulinemia appears to be an additional factor important for disease expression.

Expression of Type III Hyperlipoproteinemia in Apolipoprotein E2 (Arg158→Cys) Homozygotes Is Associated With Hyperinsulinemia

“…This is in line with our previous findings in a smaller group of apoE2 homozygotes. 20 Recently, Brümmer et al 23 have compared 8 type III HLP patients and 3 normolipidemic E2/2 subjects. Their study demonstrated increased postprandial insulin levels but normal fasting insulin levels in type III HLP patients, which were most likely due to the small sample size.…”

A systematic review and meta-analysis of the relationship between lipoprotein lipase Asn291Ser variant and diseases

“…Based on 13 studies published up to 1997 (27), Asn291Ser heterozygous carriers had an average increase in plasma TG of 31% and an average decrease in HDL-C of 0.12 mM (P , 0.001). However, since then, a number of other studies have been published in which no association was observed (10,18,20,21,24). In addition to study power and other methodological issues, interactions with important dyslipidemic risk factors such as increasing age and weight gain could have resulted in heterogeneous findings.…”

A Case of Familial Dysbetalipoproteinemia with Very Low Serum High-Density Lipoprotein-Cholesterol: Response to Atorvastatin Therapy

“…The secondary types include: (1) an "acquired secondary" subtype, which is seen in patients who are hypothyroid, have poorly-controlled diabetes mellitus, are uremic, have dysglobulinemia, or are treated with ␤-blockers and/or thiazides [19][20][21], and (2) a familial secondary subtype that is seen in conjunction with other primary hyperlipidemias, such as familial combined hyperlipidemia and hepatic lipase deficiency [8,20]. The primary types of dysbetalipoproteinemias are of familial nature, and include patients that are: (1) homozygous for the ⑀2 locus of apo-E (⑀2/⑀2 genotype) [5,8,9]; (2) homozygous for other, less common apo-E variants that have low affinity to the hepatic apo-B/apo-E (LDL) receptors [4,[22][23][24]; and (3) patients with apo-E deficiency [25].…”

“…Apo-E plays an important role in lipoprotein metabolism caused by its location on apo-Bcontaining particles, but is also found on some high-density lipoprotein (HDL) particles. The development of FDB is frequently secondary to other concomitant genetic or environmental factors, which lead to the emergence of the overt phenotype of this particular dyslipidemia [3,9]. With regard to HDL levels in patients with FDB, these are usually only mildly decreased, and often correlate inversely with serum TG levels [10].…”

“…The most common cause of the dysfunctional apo-E is the presence of the ⑀2 allele under homozygous conditions (⑀2/ ⑀2 genotype); this allele is a variant of the most prevalent one in the general population, which is ⑀3 [4,5,9]. Apo-E plays an important role in lipoprotein metabolism caused by its location on apo-Bcontaining particles, but is also found on some high-density lipoprotein (HDL) particles.…”