**3. The biosynthesis of apo(a)**

since commonly accepted reference materials and standardized analytical methods were lacking. However, newer commercial assays based on nephelometry or tur‐ bidimetry, or ELISA using monoclonal antibodies that recognize single epitopes in

Lipoprotein(a) [Lp(a)] was uncovered in 1963, and its role in atherogenesis has been a matter of debate for many years. This was caused to a certain extent by the fact that the function of Lp(a) was—and still is—unknown. Also, there exists no specific therapy for reducing elevated blood levels of Lp(a). Lp(a) consists of an LDL-like core and a specific antigen, apo(a). Apo(a) exhibits a great homology to plasminogen. For this reason, it was long believed that Lp(a) may play a role in hemostasis and fibrinolysis. There are numerous publications dealing with the role of Lp(a) in hemostasis (reviewed in ref. [1]) providing evidence that the atherogenicity of Lp(a) in fact might be due to a certain extent to pathophysiological effects in fibrinolysis. These findings, however, appear to be of little relevance for practical considerations. Of much greater importance is the causal relationship of elevated plasma Lp(a) with the incidence of athero‐ sclerosis, coronary heart diseases and stroke [2–4]. Of note, on the other hand, are the findings that plasma Lp(a) levels rise with age, i.e. that nonagenarians exhibit significantly higher Lp(a)

The protein part of Lp(a) consists of two main components, apoB-100 and apo(a) [6]. ApoB-100, the main component of LDL, is biosynthesized in the liver and LDL is the end-product of VLDL catabolism. Yet, LDL also appears to be synthesized directly and secreted from the liver. Liver LDL, however, displays a different composition from VLDL-derived LDL. Apo(a) consists of 11 unique "kringle-IV's" (K-IV) that are highly homologous to kringle-4 of plasminogen. In addition, apo(a) has a variable number of so-called repetitive K-IVs, which is one of the main puzzles in the immunochemical quantification of Lp(a) (see below). In addition to the presence of K-IVs, apo(a) possesses one kringle-V and a nonactive protease domain; further details on the structure of apo(a) may be found in ref. [7]. The exact mode of the assembly of Lp(a) from LDL and apo(a) might be irrelevant for Lp(a) quantifications, yet it has important implications for the development of Lp(a)-lowering drugs and the interpretation of their mode of action. Mixing recombinant apo(a) with LDL in the test tube and incubation for a few minutes leads to the formation of an intact Lp(a) particle that is indistinguishable from native Lp(a). This led to the assumption that the assembly of Lp(a) takes part outside the liver in circulating blood. Turnover studies carried out in the laboratory of H. Dieplinger (Innsbruck), on the other hand, revealed that the synthesis rate of protein components of Lp(a), i.e. apoB-100 and apo(a), are

apo(a), warrant comparable interlaboratory results.

plasma levels than younger generations [5].

**2. Lp(a) metabolism**

**1. Introduction**

138 Lipoproteins - From Bench to Bedside

**Keywords:** Metabolism, Fibrinolysis, Reference values, Medication

The locus for the apo(a) gene is situated at chromosome 6 (6q26–q276). The biosynthesis of apo(a) is characteristic of that for any glycoprotein, and the negative correlation of the number of K-IV repeats with the plasma concentration has been explained by longer cellular residence times causing a more efficient intracellular degradation of large molecular weight apo(a) isoforms.

The rate of apo(a) biosynthesis, on the other hand, is significantly influenced by the promoter activity and its activation by transcription factors and nuclear receptors. We provided evidence that the apo(a) promoter contains response elements for >70 transcription factors including HNFs, FXR, PPARs, RXR, SREBPs, CCAAT-Enhancer, IL-6 in addition to numerous others that play important roles in the lipid and lipoprotein metabolism [10]. The presence of these multiple transcription factor binding sites led to the assumption that the regulation of apo(a) transcription might be complex and influenced by numerous metabolic features. Our research group was in fact the first to characterize important response elements in the apo(a) promoter that are key for apo(a) transcription and the abundance of apo(a) in blood plasma [10]. The most significant response element is that of HNF4α at position –826 to –814 in the apo(a) promoter. HNF4α βνδνγ is competed by farnesoid-X receptor (FXR), a nuclear receptor that plays an important role in bile acid metabolism. Thus, elevated plasma bile acid levels that activate FXR lead to a profound reduction of Lp(a) biosynthesis. These metabolic relationships are schematically displayed in Fig. 1.
