Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecular mechanisms regulating the amount of dietary cholesterol retained by the body, as well as the body's ability to exclude other dietary sterols selectively, are poorly understood. An average Western diet will contain approximately 250-500 mg of dietary cholesterol and approximately 200-400 mg of non-cholesterol sterols, of which plant sterols are the major constituents. Approximately 50-60% of dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. There thus exists a subtle mechanism that allows the body to distinguish between cholesterol and non-cholesterol sterols. In sitosterolemia, a rare autosomal recessive disorder, affected individuals hyperabsorb and retain not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine. Consequently, patients with this disease have very high levels of plant sterols in the plasma, and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. The STSL locus has been mapped to human chromosome 2p21. Mutations in two tandem ABC genes, ABCG5 and ABCG8, encoding sterolin-1 and -2, respectively, are now known to be mutant in sitosterolemia. The identification of these genes should now lead to a better understanding of the molecular mechanism(s) governing the highly selective absorption and retention of cholesterol by the body. Indeed, it is the very existence of this disease that has given credence to the hypothesis that there is a molecular pathway that regulates dietary cholesterol absorption and sterol excretion by the body.
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PMID:Genetic basis of sitosterolemia. 1126 85

Sitosterolemia is a rare autosomal recessive disorder characterized by (a) intestinal hyperabsorption of all sterols, including cholesterol and plant and shellfish sterols, and (b) impaired ability to excrete sterols into bile. Patients with this disease have expanded body pools of cholesterol and very elevated plasma plant-sterol species and frequently develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. In previous studies, we have mapped the STSL locus to human chromosome 2p21. Recently, we reported that a novel member of the ABC-transporter family, named "sterolin-1" and encoded by ABCG5, is mutated in 9 unrelated families with sitosterolemia; in the remaining 25 families, no mutations in sterolin-1 could be identified. We identified another ABC transporter, located <400 bp upstream of sterolin-1, in the opposite orientation. Mutational analyses revealed that this highly homologous protein, termed "sterolin-2" and encoded by ABCG8, is mutated in the remaining pedigrees. Thus, two highly homologous genes, located in a head-to-head configuration on chromosome 2p21, are involved as causes of sitosterolemia. These studies indicate that both sterolin-1 and sterolin-2 are indispensable for the regulation of sterol absorption and excretion. Identification of sterolin-1 and sterolin-2 as critical players in the regulation of dietary-sterol absorption and excretion identifies a new pathway of sterol transport.
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PMID:Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively. 1145 59

PURPOSE OF REVIEW This review discusses recent progress in the role of ATP-binding cassette proteins ABCG5 and G8 in dietary sterol absorption, excretion and pathogenesis of cardiovascular disease. RECENT FINDINGS Identification of the genetic defect(s) underlying sitosterolemia has led to a renewed interest in the mechanisms of sterol absorption and biliary excretion. Mutations in ABCG5 (encoding sterolin-1) or ABCG8 (encoding sterolin-2) cause this disease. These proteins are thought to function by preventing dietary noncholesterol sterols from being retained by the body and for cholesterol excretion into bile. SUMMARY Despite improvements in treatments for hypercholesterolemia with cholesterol lowering agents, cardiovascular disease still remains highly prevalent. This has prompted many to consider that molecules other than cholesterol may be better biomarkers for this disease and targeting these more directly may allow us to develop more effective therapies. Ideally, if such a biomarker were also the bioactive molecule that is key to initiating/propagating the atherosclerosis pathogenic pathway, this would allow us to develop an optimal predictor and monitor of the disease process. One source of such molecules could come from our diet, with potential candidates such as noncholesterol sterols, oxysterols, oxidized sterols or some as yet unidentified dietary bioactive molecule. Nature has evolved a protective mechanism by which such molecules are kept out of the body, thereby reducing the negative effects of these compounds. The newly identified sterolin proteins involved in the absorption and excretion of dietary sterols may fit this bill. If so, we would speculate that a better biomarker may be lurking within their substrate specificities.
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PMID:Genetic defenses against noncholesterol sterols. 1286 30

Sitosterol is the most abundant plant sterol found in our diet. Sitosterolemia (OMIM 210250), also known as phytosterolaemia, is a rare autosomal recessive disease caused by the inability to efficiently excrete plant sterol, and is characterized by cutaneous xanthomas and accelerated atherosclerosis. Sitosterolaemia is caused by homozygous or compound heterozygous mutations in either ABCG5 or ABCG8 (both on chromosome 2p21), which encode the sterol efflux transporter ABCG5 (sterolin-1) and ABCG8 (sterolin-2), respectively. To investigate a Tunisian family with several members who manifested with generalized cutaneous xanthomas, whereas others had only isolated xanthelasmas. Genetic analysis was performed based on exome sequencing of DNA obtained from five affected individuals and one unaffected individual from a Tunisian family.
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PMID:Mutations in the ABCG8 gene are associated with sitosterolaemia in the homozygous form and xanthelasmas in the heterozygous form. 2873 49