Genetic basis of sitosterolemia

The molecular mechanisms regulating the amount of dietary cholesterol retai ned by the body, as well as the body's ability to exclude other dietary ste rols selectively, are poorly understood. An average Western diet will conta in approximately 250-500 mg of dietary cholesterol and approximately 200-40 0 mg of non-cholesterol sterols, of which plant sterols are the major const ituents. Approximately 50-60% of dietary cholesterol is absorbed and retain ed by the normal human body, but less than 1% of the non-cholesterol sterol s are retained. There thus exists a subtle mechanism that allows the body t o distinguish between cholesterol and non-cholesterol sterols, In sitostero lemia, a rare autosomal recessive disorder, affected individuals hyperabsor b and retain not only cholesterol but also all other sterols, including pla nt and shellfish sterols from the intestine. Consequently, patients with th is disease have very high levels of plant sterols in the plasma, and develo p tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. The STSL locus has been mapped to human chromosom e 2p21. Mutations in two tandem ABC genes, ABCG5 and ABCG8, encoding sterol in-1 and -2, respectively, are now known to be mutant in sitosterolemia. Th e identification of these genes should now lead to a better understanding o f the molecular mechanism(s) governing the highly selective absorption and retention of cholesterol by the body. Indeed, it is the very existence of t his disease that has given credence to the hypothesis that there is a molec ular pathway that regulates dietary cholesterol absorption and sterol excre tion by the body. Curr Opin Lipidol 12:141-149. (C) 2001 Lippincott William s & Wilkins.