Familial hypobetalipoproteinemia and abetalipoproteinemia
Familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL) are rare diseases that cause hypocholesterolemia. Studying FHBL and ABL is essential to furthering the field of cholesterol research and has provided many therapeutic targets for hypercholesterolemia. ABL is an autosomal, recessive disease caused by a mutation in MTP, a chaperone protein in the ER that helps fold nascent apoB and transfers lipids onto apoB. FHBL is an autosomal, codominant disease caused by a mutation in APOB, which usually causes a truncated apoB with loss-of-function. ABL and homozygous FHBL have the same clinical symptoms: steatorrhea, neurological dysfunction, vision problems, and non-alcoholic fatty liver. Implementing a low-fat diet routine along with vitamin supplementations will ameliorate most symptoms except for hepatic steatosis. Both ABL and FHBL carry a reduced risk of cardiovascular diseases due to the reduction of atherosclerosis. Many new therapeutic targets for hypercholesterolemia have been inspired by FHBL and ABL. Lomitapide is an MTP (microsomal triglyceride transfer protein) inhibitor that mimics ABL's mutant mechanism. Mipomersen is an apoB synthesis inhibitor, which mimics FHBL's mutant mechanism. The purpose of both drugs is to treat familial hypercholesterolemia. This literature review suggests other targets: a molecule to permanently bind apoB to MTP which mimics an FHBL mutation, a molecule to prevent PDI from binding to the large M subunit in the heterodimer MTP, and a method to truncate apoB to mimic FHBL mutations. Two new recently-discovered diseases have similar phenotypes as ABL and FHBL: PCSK9 deficiency and familial combined hypolipidemia. Both cause hypocholesterolemia. However, PCSK9 does not have the negative systemic effects such as steatorrhea and neurological dysfunction. In addition, no fatty liver develops. More research into these new diseases can contribute to the field of hypocholesterolemia, which provides new therapeutic targets for hypercholesterolemia.