Last Updated: May 7, 2024
Clinical Features of PCSK9-Mediated FHBL
Familial hypobetalipoproteinemia syndrome (FHBL) is causally associated with increased hepatic fat content. The most common mutations associated with FHBL are truncating mutations in the APOB gene. Autosomal dominant mutations in the gene (PCSK9) encoding proprotein convertase subtilisin/kexin type 9 are also associated with FHBL. The PCSK9 mutations associated with FHBL are all loss-of-function mutations.
In the vast majority of FHBL patients hepatic triglyceride is, on average, three-fold higher in heterozygous individuals harboring inactivating mutations in the APOB gene compared to healthy individuals. Hepatic steatosis in FHBL results from defective export of triglyceride from the liver in the absence of other metabolic derangements. This feature of FHBL allowed for examination of the role of hepatic fat content and insulin resistance. Although moderate to severe intrahepatic triglyceride levels are found in FHBL patients there does not appear to result in hepatic or peripheral (muscle or adipose tissue) insulin resistance.
PCSK9 Functions
PCSK9 is secreted by the liver and it binds to LDL-LDL receptor (LDL-LDLR) complexes on plasma membranes of hepatocytes. Following endocytosis of the LDL-LDLR-PCSK9 complexes into hepatocytes, PSCK9 degrades the LDL receptor (LDLR), thereby reducing the recycling of the LDLR to the plasma membrane. Loss-of-function mutations in the PCSK9 gene, therefore, result in increased LDL receptor density on hepatocytes allowing for increased removal of LDL from the blood.
Loss-of-function mutations in the PCSK9 gene prevent the PCSK9-mediated degradation of the LDL receptor and thus increase uptake of LDL by the liver. These mutations result in a 30–70% reduction in plasma LDL-cholesterol levels and FHBL. In contrast to APOB gene mutations, PCSK9 mutations are not associated with any significant clinical pathology. Indeed, patients with PCSK9 mutations have been associated with a decreased risk of cardiovascular disease.
Molecular Biology of PCSK9
The PCSK9 gene is located on chromosome 1p32.3 and is composed of 14 exons that generate nine alternatively spliced mRNAs, each of which encode a distinct precursor protein isoform.
The frequency of loss-of-function mutations in the PCSK9 gene is on the order of 1:1,000 to 1:3,000. Common mutations in PCSK9 that result in FHBL are missense mutations at amino acid 46 (R46L), 106 (G106R), and 237 (R237W).
Pharmacology of PCSK9
The loss-of-function mutations in PCSK9 that have been identified are all associated with low LDL cholesterol (LDL-C) levels, a markedly reduced risk for coronary artery atherosclerosis, and otherwise normal health. Identification of individuals with loss-of-function mutations in the PCSK9 gene, and their attendant low serum LDL-C levels indicated that developing drugs to inhibit the normal function of PCSK9 would have therapeutic advantages in the treatment of patients with hypercholesterolemias.
Currently two monoclonal antibody-based therapies have been approved by the US FDA for use in patients that are heterozygous for mutations causing familial hypercholesterolemia. These fully human monoclonal antibody-based therapies are evolocumab (Repatha®) and alirocumab (Praluent®).