Gene

Internal medicine

Phenotype

Endocrinology

Blood lipids

Cholesterol

Genetic disorder

Familial hypercholesterolemia

Lipoprotein

PCSK9

Lipid Metabolism Disorder

LDL receptor

Genetics

Bioinformatics

Apolipoprotein B

Medicine

Biology

Journal of Lipid Research

Familial hypercholesterolemia (FH) is one of the most common genetic disorders in humans. It is an extremely atherogenic metabolic disorder characterized by lifelong elevations of circulating LDL-C levels often leading to premature cardiovascular events. In this review, we discuss the clinical phenotypes of heterozygous and homozygous FH, the genetic variants in four genes (LDLR/APOB/PCSK9/LDLRAP1) underpinning the FH phenotype as well as the most recent in vitro experimental approaches used to investigate molecular defects affecting the LDL receptor pathway. In addition, we review perturbations in the metabolism of lipoproteins other than LDL in FH, with a major focus on lipoprotein (a). Finally, we discuss the mode of action and efficacy of many of the currently approved hypocholesterolemic agents used to treat patients with FH, with a special emphasis on the treatment of phenotypically more severe forms of FH.

Lipoprotein metabolism in familial hypercholesterolemia