Lipoprotein(a) the Insurgent: A New Insight into the Structure, Function, Metabolism, Pathogenicity, and Medications Affecting Lipoprotein(a) Molecule

Figure 3

Model for the metabolism of apo(a). 1—Lipoprotein (a) production (hepatocyte level). Four stages are likely responsible for apo(a) Lp(a) production in liver cells: (A) transcription of the apo(a) gene and apo(a) mRNA stability in the nucleus; (B) influence of apo(a) translation on the production rate; (c) in the ER, posttranslation modifications and folding of apo(a) kringles; (D) Golgi-specific addition and modification of apo(a) carbohydrates; and (E) transport to the cell surface. 2—Assembly of Lp(a): The site of Lp(a) assembly is controversial. (A) cell surface. (B) The space of Disse. (C) Plasma. 3—Apo(a) associates with a recently made TG-abundant molecule to form Lp(a) with VLDL properties and/or with a cholesterol-abundant molecule with LDL properties. 4—TG-abundant Lp(a) may be transformed into a cholesterol-abundant molecule with LDL properties. 5—Catabolism and clearance: The two Lp(a) components become separated. The generation of apo(a) fragments is most likely from proteolytic cleavage by elastases or metalloproteinases secreted by cells in the arterial wall. (5—A) This permits apo(a) to unite the apo(a) pool recently produced by the hepatocytes. (5-B) Hepatocyte internalization and uptake by megalin, gp330 receptor, macrophage scavenger receptor-BI, lipoprotein receptor, VLDL receptor, PlgRKT receptor, asialoglycoprotein receptor (ASGPR), and LDLR. (5-B) Kidney cellular internalization and uptake. (5-C) Vascular wall deposition. Solid lines represent metabolic pathways; dotted lines represent hypothesized metabolic pathways.