Lipoprotein(a): structural implications for pathophysiology.

Abstract

The assembly between a low-density lipoprotein particle and apolipoprotein(a), a highly carbohydrate-rich protein, gives origin to a peculiar class of lipoproteins, only found in the hedgehog, primates, and humans, termed lipoprotein(a). Apolipoprotein(a), which shares a high degree of sequence homology with the fibrinolytic proenzyme plasminogen, is linked to the apolipoprotein B-100 component of low-density lipoprotein via a disulfide bond and confers distinct biochemical and metabolic properties to lipoprotein(a). Because of its peculiar structural features and the observed correlation between high lipoprotein(a) levels and the development of a variety of atherosclerotic disorders, this lipoprotein has become the focus of an intense research effort. Although accumulation of lipoprotein(a) in the vessel wall at sites of vascular injury has been clearly evidenced, the mechanism(s) by which lipoprotein(a) exerts its pathogenic effect in this milieu remain largely unknown. It has been hypothesized that the pathological effect of lipoprotein(a) is related either to its similarity to low-density lipoprotein (i.e., a pro-atherogenic effect) or to the apolipoprotein(a) similarity to plasminogen (i.e., a pro-thrombotic/anti-fibrinolytic effect). However, it is probable that both components contribute to the pathogenicity of lipoprotein(a). The fact that lipoprotein(a) levels are largely genetically determined, varying widely among individuals and racial groups, adds additional elements to the scientific interest that surrounds this lipoprotein. Both clinical and biochemical studies of lipoprotein(a) have been complicated by the high degree of structural heterogeneity of apolipoprotein(a), which is considered the most polymorphic protein in human plasma. Our aim in this paper is to provide an overview of the most salient structural features of lipoprotein(a) and their possible pathophysiological implications.