Diabetologie und Stoffwechsel 2011; 6 - P106
DOI: 10.1055/s-0031-1277377

Apolipoprotein A5 (apoA5), besides accelerating plasma triglyceride hydrolysis, mediates triglyceride reduction via an LDL receptor related protein 1 (LRP1) dependent pathway

M Merkel 1, K Brügelmann 2, J Heeren 2
  • 1Asklepios Clinic St. Georg, Department of Internal Medicine, Hamburg, Germany
  • 2University Hospital Hamburg-Eppendorf, Institute for Biochemistry – IBM2, Hamburg, Germany

Aims: Apolipoprotein A5 (apoA5) is regulates plasma triglyceride (TG) levels. Genetic aberrations (SNP's) in its gene lead to increased plasma TG in humans; apoA5 deficiency by structural mutations yields into severe hypertriglyceridemia type I or V. ApoA5 reduces plasma TG levels by activating or stabilizing endothelial lipoprotein lipase (LPL). However, due to its binding properties and its high intra-hepatocellular concentration it had been postulated, that apoA5 may also mediate hepatic lipoprotein uptake. A possible involvement of LDL receptor related protein 1 (LRP1) during this process is the focus of the present study.

Methods: Mice being wild type (WT) or transgenic for apoA5 were crossed onto a homozygote LRP1flox/flox background. Hepatic LRP1 expression was ablated specifically in the liver either by adenoviral hepatic Cre expression or by crossbreeding with mice with transgenic expression of an alb promoter driven Cre gene. Thus, two comparable models were created. For each model, the lipid metabolism of four mouse groups was compared (littermate controls): With and without transgenic expression of apoA5 both in wild type and in liver LPR1 deficient mice.

Results: As previously reported, on the WT background, transgenic apoA5 expression reduced plasma TG by 61% due to VLDL removal. However, without LRP1 in the liver, apoA5 was not at all able to reduce plasma TG. This was the case both with adenoviral and with transgenic hepatic Cre expression and LRP1 ablation. Metabolic turnover and organ uptake studies with lipoproteins (LDL, VLDL, chylomicrons radioactively labelled at their triglyceride and apoprotein residues) showed a reduced effect of apoA5 on hepatic lipoprotein uptake in liver LPR1 deficient mice compared that in wild type LRP1 mice.

Conclusion: Surprisingly, LRP1 plays a significant role for apoA5 mediated TG reduction. However, whether this is indeed due to LRP1 mediated particle uptake or rather a more complex process possibly with the involvement of lipoprotein bound LPL, is currently being investigated in primary hepatocytes.