LDL Receptor and Its Role in Inherited Disease

Abstract

The low‐density lipoprotein (LDL) receptor mediates the specific uptake of LDL from the circulation and its intracellular degradation by a process known as the LDL receptor pathway. LDL receptor gene expression is regulated by intracellular sterol content, and is limited mainly to the liver in vivo . Mutations in LDLR , the gene encoding the LDL receptor, cause familial hypercholesterolaemia (FH), a dominantly inherited disease where accumulation of LDL in the circulation increases the risk of coronary heart disease. Defects in other genes, including APOB , encoding the ligand for the LDL receptor, ARH , encoding a protein required for its internalisation and proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), encoding a protein that reduces LDL receptor protein levels, cause a similar disorder because the encoded proteins are involved in the LDL receptor pathway. FH can readily be treated with cholesterol‐lowering drugs to reduce cardiovascular risk effectively, and identification of the causal genetic defect allows unequivocal and early diagnosis. Key Concepts: The LDL receptor mediates specific uptake and intracellular degradation of serum LDL. Inherited defects in the LDL receptor pathway cause familial hypercholesterolaemia (FH), characterised by increased serum LDL and increased risk of coronary heart disease. Most FH patients have mutations in LDLR , but defects in other genes cause a similar disorder. A recessive form of FH is caused by null mutations in ARH, a clathrin adaptor protein required for LDL receptor internalisation. A dominant form of FH is caused by gain‐of‐function mutations in PCSK9 , which encodes a protein that promotes degradation of LDL receptor protein. Dominant loss‐of‐function mutations in PCSK9 reduce serum cholesterol and risk of coronary heart disease. One relatively common dominant mutation in APOB , encoding the ligand for the LDL receptor, causes familial defective apoB (FDB). LDLR transcription is regulated by sterol response element‐binding proteins (SREBP) in a complex mechanism involving several other proteins. FH can readily be treated with cholesterol‐lowering drug therapy to abolish the increased risk of coronary disease, but is currently under‐diagnosed. Identifying causal mutations in known patients and screening their relatives should identify more affected individuals.