Abstract
BackgroundThe Lp(a) lipoprotein (Lp(a)) consists of the polymorphic glycoprotein apolipoprotein(a) (apo(a)), which is attached by a disulfide bond to apolipoprotein B (apoB). Apo(a), which has high homology with plasminogen, is present only in primates and hedgehogs. However, transgenic mice and rabbits with high serum apo(a) levels exist. Liver is the main site for apo(a) synthesis, but the site of removal is uncertain. To examine differences between transgenic mice expressing the LPA gene and mice capable of forming Lp(a) particles, LPA-YAC transgenic mice and hAPOB transgenic mice were crossed and their offspring examined.ResultsComparison of LPA-YAC with LPA-YAC/hAPOB transgenic mice showed that LPA-YAC/hAPOB transgenic mice have higher serum total apo(a) and total cholesterol level than mice lacking the hAPOB gene. However, hepatic apo(a) mRNA level was higher in LPA-YAC transgenic mice than in LPA-YAC/hAPOB transgenic mice. Feeding of a high-cholesterol/high-fat diet to male LPA-YAC transgenic mice with or without the hAPOB gene resulted in reduced serum total apo(a) and hepatic apo(a) mRNA level.ConclusionIn conclusion, the higher serum total apo(a) level in LPA-YAC/hAPOB transgenic mice than in LPA-YAC transgenic mice is not caused by increased apo(a) synthesis. Lower hepatic apo(a) mRNA level in LPA-YAC/hAPOB than in LPA-YAC transgenic mice may suggest that the increase in total apo(a) level is a result of apo(a) accumulation in serum. Furthermore, observed higher serum total cholesterol level in LPA-YAC/hAPOB transgenic mice than either in wild type or LPA-YAC transgenic mice may further suggest that human APOB transgenicity is a factor that contributes to increased serum total apo(a) and cholesterol levels. Our results on reduced serum total apo(a) and hepatic apo(a) mRNA levels in HCHF fed male LPA-YAC transgenic mice confirm earlier findings in females, and show that there are no sex difference in mechanisms for lowering apo(a) level in response to HCHF feeding.
Highlights
The Lp(a) lipoprotein (Lp(a)) consists of the polymorphic glycoprotein apolipoprotein(a) (apo(a)), which is attached by a disulfide bond to apolipoprotein B
We showed that feeding of a high-cholesterol/highfat (HCHF) diet to male LPA-yeast artificial chromosome (LPA-YAC) transgenic mice, which on a standard mouse diet exhibit much lower serum total apo(a) level than female mice, reduced serum total apo(a) and hepatic apo(a) mRNA level in a similar manner as previously shown in female mice [19,20]
Serum apo(a) level On a regular RMI(E)SQC mouse diet serum total apo(a) level was significantly higher in LPA-YAC/human APOB (hAPOB) transgenic mice than in LPA-YAC transgenic mice (P < 0.05, figure 1) and serum total apo(a) levels were higher in female transgenic mice than in respective male transgenic mice (P < 0.005, figure 1)
Summary
The Lp(a) lipoprotein (Lp(a)) consists of the polymorphic glycoprotein apolipoprotein(a) (apo(a)), which is attached by a disulfide bond to apolipoprotein B (apoB). The intact Lp(a) molecule consists of the highly polymorphic glycoprotein apolipoprotein(a) (apo(a)), which is attached through a disulfide bond to apolipoprotein B-100 (apoB100) of low density lipoprotein (LDL). Gene encoding for apo(a) (LPA), which expression is mainly confined to the liver, is tightly linked to plasminogen (PLG) gene on chromosome 6 and is homologous to PLG [4,5]. This sequence similarity indicates that the human LPA gene evolved from a duplicated PLG gene during primate evolution [6,7]. In addition to humans, Old World monkeys, great apes and hedgehogs are the only species, which express LPA naturally [8,9,10]
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