Figure 1

Molecular Pathways of Disease in Familial Hypercholesterolemia (1) The LDL receptor on the surface of hepatocytes binds ApoB-100 of the LDL particle forming a complex. (2) A clathrin-coated pit is formed and the ligand-receptor complex is endocytosed via interactions involving the LDLR Adaptor Protein 1 (LDLRAP1). (3) Inside the hepatocyte, the complex dissociates, the LDLR recycles to the cell membrane, (4) and free cholesterol is used inside the cell. (5) PCSK9 serves as a post-transcriptional inhibitor of LDLR. It is secreted and inhibits LDLR through cell-surface interactions. (6) The presence of an intracellular pathway for PCSK9-mediated LDLR inhibition is still a subject of controversy. (7) In response to decreased cholesterol such as during treatment with statins, Steroid Response Element Binding Protein (SREBP) binds to the Steroid Response Element (SRE) on the DNA and induces the transcription of the LDLR. (8) The sterol-responsive nuclear receptor LXR on the other hand responds to increased intracellular cholesterol inducing the transcription of IDOL, a recently discovered molecule that induces the ubiquitin-mediated degradation of the LDLR. Clouds in the figure refer to genes in which mutations have been associated with increased LDL-C levels.