Major monogenic determinants of familial hypercholesterolemia [3, 4, 5, 6, 7, 8]. LDLRs are located on the hepatocyte surface and bind LDL via apoB, resulting in receptor-mediated endocytosis facilitated by LDLRAP1. The LDL-LDLR complex is then transported to an early endosome which acidifies, resulting in a conformational change of the LDLR and subsequent offloading of the LDL particle. The endosome carrying the now free LDL particle fuses with a lysosome, where its lipid cargo is repurposed in a myriad of ways depending on cellular needs. At the same time, the LDLR is recycled back to the hepatocyte surface for further rounds of LDL particle clearance. Another key regulator of LDLR recycling and cholesterol homeostasis is PCSK9, a low-abundance plasma protein that is secreted predominantly by the liver and can bind to the LDLR. With PCSK9 bound to LDLR, the same process of clathrin-mediated receptor endocytosis occurs; however, PCSK9 prevents the conformational change in LDLR from occurring. Without the structural change in LDLR, the LDL particle is not offloaded, and the entire LDL-PCSK9-LDLR complex fuses with a lysosome for destruction, preventing LDLR recycling. Thus, loss of function of LDLR, apoB, and LDLRAP1, or gain in function of PCSK9, results in decreased LDL plasma clearance, leading to FH. Abbreviations: LDLR, low-density lipoprotein receptor; LDL, low-density lipoprotein; apoB, apolipoprotein B; LDLRAP1, LDLR adaptor protein-1; PCSK9, proprotein convertase subtilisin/kexin type 9; ER, endoplasmic reticulum; Golgi, Golgi apparatus.