**4. The Lp(a) catabolism**

There exist numerous gaps not only in the understanding of Lp(a) biosynthesis but even more so in Lp(a) catabolism. Very little is known on the site of uptake, the mode of cell binding, internalization and intracellular degradation. *In vivo* studies have been performed mostly on animals that by themselves do not produce Lp(a). These latter studies revealed that >50% of Lp(a) is taken up by the liver and that protein degradation products are secreted into bile [11].

**Figure 1.** Inhibition of apo(a) transcription by bile acids. Chenodeoxycholic acid (CDCA), the FXR agonist with the highest affinity in humans, binds and activates FXR leading to a displacement of that complex from the cytoplasm to the nucleus. The complex interferes with HNF4α binding to DR-1, a key response element in the apo(a) promoter and in turn silences apo(a) transcription. With permission of the Medical University of Graz (copyrights held by the MUG Graz, Austria).

Significant amounts of radioactivity from labeled Lp(a), however, were also found in kidney, spleen, lung and pancreas, yet it is unknown whether these organs are of relevance for Lp(a) catabolism in humans. Since the liver is the principal organ for the LDL-receptor-mediated catabolism of apoB-containing lipoproteins, it was of interest to study this particular pathway for Lp(a) catabolism. *In vivo* studies carried out in our laboratory as well as by other groups, however, revealed that Lp(a) only has a low affinity to the LDL-R. The main argument for this allegation is the fact that Lp(a) is catabolized in homozygous FH patients with the same rate as compared to healthy control individuals [12]. Since pathways involved in Lp(a) catabolism —and in particular the role of specific receptors—is of eminent importance for strategies to develop Lp(a)-lowering drugs, many attempts have been made to identify binding proteins (receptors) that might be specific for Lp(a). Actually there is hardly any lipoprotein receptor that had not been found to bind Lp(a), including LRP, VLDL-R, asialo-glycoprotein receptor, different scavenger receptors and others. Unfortunately, all these results are based on *in vitro* studies that may have little relevance for the *in vivo* situation. One pathway that appears to be a hot candidate for Lp(a) catabolism is the binding of apo(a) kringle to lysine (Lys)-rich cell surface proteins. Along these lines, we actually demonstrated in previous experiments that feeding of Lys analogues such as tranexamic acid or δ-amino valeric acid to transgenic apo(a) or Lp(a) mice increased the Lp(a) plasma levels by a factor of 1.5–2, and this correlated with a lower cell uptake and a higher Lp(a) degradation [13].
