Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype

Area of Science:

• Biochemistry
• Genetics
• Metabolic Disorders

Background:

• Bile acid synthesis is crucial for cholesterol homeostasis.
• The CYP7A1 gene encodes cholesterol 7alpha-hydroxylase, a key enzyme in bile acid production.

Observation:

• A novel metabolic disorder characterized by hyperlipidemia was identified.
• This disorder resulted from a homozygous deletion mutation in the CYP7A1 gene, causing a frameshift (L413fsX414) and loss of enzyme function.

Findings:

• Homozygous subjects exhibited significantly elevated LDL cholesterol levels.
• Liver biopsies revealed doubled hepatic cholesterol, deficient bile acid excretion, and alternative pathway upregulation.
• Affected individuals experienced hypertriglyceridemia, premature gallstones, and statin-resistant hyperlipidemia.

Implications:

• This study identifies a new genetic cause of hyperlipidemia and highlights the role of CYP7A1 in cholesterol metabolism.
• The findings suggest CYP7A1 mutations can lead to severe metabolic disturbances, including cardiovascular complications.
• The codominant inheritance pattern indicates heterozygous carriers also experience hyperlipidemia.