Inhibition of Apolipoprotein(a) Synthesis by Farnesoid X Receptor and Fibroblast Growth Factor 15/19

Abstract

Lipoprotein(a), or Lp(a), is a plasma lipoprotein that accumulates in concentrations ranging from undetectable to as high as 200 mg/dL, mostly depending on the synthesis rate of its unique protein, apo(a), which consists of multiple repetitions of kringle IV, type 2 of plasminogen.1 Additionally, plasma levels of Lp(a) are inversely proportional to the size of the apo(a) isoform, which is genetically determined.2 Considering that cholesterol represents about one fifth of the particle, Lp(a) can be equivalent to an extra 40 mg/dL of low-density lipoprotein (LDL) cholesterol in some individuals. The complex is the result of a covalent association between apoB100 and the function-free apo(a). The size of this lipoprotein ranges from that of a large high-density lipoprotein (HDL) to that of a small remnant depending on its triglyceride content. It is an apoB-containing lipoprotein and therefore viewed as an atherogenic particle. Because apo(a) does not form Lp(a) in murine plasma, development of a transgenic mouse model has required the concomitant expression of human apo(a) and apoB100.3 Apo(a) binds via a single disulfide bridge to the carboxyl-terminus of apoB100 and thus cannot associate with chylomicrons, which only contain apoB48.4 Also, apo(a) preferentially binds apoB100 of LDL-sized particles, although the linkage between the 2 proteins is likely to take place on the surface of hepatocytes, which produce exclusively VLDL-sized particles.5 On the clearance front, Lp(a) does not bind to the LDL receptor, and only modest increases in Lp(a) levels are seen in patients with familial hypercholesterolemia.6 This means that cholesterol-lowering agents acting more or less directly via upregulation of the LDL receptor (statins, resins, and cholesterol absorption inhibitors) have modest to no effects or may even raise plasma Lp(a) levels.7–9 Other agents, such as fibrates and niacins, share similar lipid-modulating effects (decreasing triglycerides, …