Cholesterol Biosynthesis Metabolites

Cholesterol is an important structural component of cellular membranes, where it plays a role in modulating membrane fluidity and phase transitions, and, together with sphingomyelin, forms lipid rafts or caveolae, which are sites where proteins involved in diverse signaling pathways become concentrated. Cholesterol is also a precursor of oxysterols, steroid hormones, and bile acids. Mammalian cells may acquire cholesterol via receptor-mediated uptake as well as via the isoprenoid/cholesterol biosynthesis pathway. Currently, 12 distinct inherited disorders have been linked to different enzyme defects in this pathway. Four of these affect enzymes in the pre-squalene part, involved in the synthesis of all sterol and non-sterol isoprenoids, while the other eight defects affect enzymes in the post-squalene part, exclusively involved in the synthesis of sterol isoprenoids. Patients afflicted with a post-squalene disorder often present with multiple morphogenic and congenital anomalies including internal organ, skeletal and/or skin abnormalities, underlining the pivotal role of cholesterol in human embryogenesis and development. Patients with a pre-squalene disorder may present with different phenotypes, but often associated with autoinflammatory symptoms. Pre-squalene disorders can be diagnosed via organic acid analysis and post-squalene disorders by sterol analysis of patient material. Additional diagnostic procedures involve enzymatic assays and/or genetic testing.