Genetic basis of sitosterolemia

Lee, Mi-Hye; Lu, Kangmo; Patel, Shailendra B.

doi:10.1097/00041433-200104000-00007

Cited by 174 publications

(122 citation statements)

References 31 publications

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“…Other studies reported the same observations [42], and mutations in two tandem ABC genes, ABCG5 and ABCG8, encoding sterolin-1 and 2, respectively, are now known to be mutant in sitosterolemia. Heterozygous individuals do not develop the disease, but present raised plasma phytosterol concentrations [64][65][66].…”

Section: Phytosterolemia or Sitosterolemia: Abcg5/g8 Mutationssupporting

confidence: 54%

Phytosterols and phytosterolemia: gene–diet interactions

et al. 2010

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Phytosterol intake is recommended as an adjunctive therapy for hypercholesterolemia, and plant sterols/stanols can reduce cholesterol absorption at the intestinal lumen through the Niemann-Pick C1 Like 1 (NPC1L1) transporter pathway by competitive solubilization in mixed micelles. Phytosterol absorption is of less magnitude than cholesterol and is preferably secreted in the intestinal lumen by ABCG5/G8 transporters. Therefore, plasma levels of plant sterols/stanols are negligible compared with cholesterol, under an ordinary diet. The mechanisms of cholesterol and plant sterols absorption and the whole-body pool of sterols are discussed in this chapter. There is controversy about treatment with statins inducing further increase in plasma non-cholesterol sterols raising concerns about the safety of supplementation of plant sterols to such drugs. In addition, increase in plant sterols has also been reported upon consumption of plant sterolenriched foods, regardless of other treatments. Rare mutations on ABCG5/G8 transporters affecting cholesterol/non-cholesterol extrusion, causing sitosterolemia with xanthomas and premature atheroslerotic disease are now known, and cholesterol/plant sterols absorption inhibitor, ezetimibe, emerges as the drug that reduces phytosterolemia and promotes xanthoma regression. On the other hand, common polymorphisms affecting the NPC1L1 transporter can interfere with the action of ezetimibe. Gene-diet interactions participate in this intricate network modulating the expression of genetic variants on specific phenotypes and can also affect the individual response to the hypolipidemic treatment. These very interesting aspects promoted a great deal of research in the field.

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Section: Phytosterolemia or Sitosterolemia: Abcg5/g8 Mutationssupporting

confidence: 54%

Phytosterols and phytosterolemia: gene–diet interactions

et al. 2010

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“…Patients with this disease develop xanthomas and premature atherosclerosis [24,25]. Affected individuals show high concentrations of plant sterols in plasma due to the fact that, in contrast to healthy subjects, they efficiently absorb these sterols from the intestine and are unable to excrete them into the bile [24,26].…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of hepatic and intestinal Abcg5 and Abcg8 expression associated with altered sterol fluxes in rats with streptozotocin-induced diabetes

Bloks¹,

Waarde²,

Verkade³

et al. 2004

Diabetologia

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Aim/hypothesis. Type I diabetes is associated with altered hepatic bile formation and increased intestinal cholesterol absorption. The aim of this study was to evaluate whether altered expression of the ATP-Binding Cassette half-transporters Abcg5 and Abcg8, recently implicated in control of both hepatobiliary cholesterol secretion and intestinal cholesterol absorption, contributes to changed cholesterol metabolism in experimental diabetes. Methods. mRNA and protein expression of Abcg5 and Abcg8 were determined in the liver and intestine of rats with streptozotozin-induced diabetes and related to relevant metabolic parameters in plasma, liver and bile. Results. Hepatic mRNA expression of both Abcg5 (−76%) and Abcg8 (−71%) was reduced in diabetic rats when compared to control rats. In spite of increased HDL cholesterol, considered a major source of biliary cholesterol, secretion of the sterol into bile relative to that of bile salts was reduced by 65% in diabetic animals. Intestinal mRNA expression of Abcg5 (−47%) and Abcg8 (−43%) as well as Abcg5 protein contents were also reduced in insulin-deficient animals. This was accompanied by a three-to four-fold increase in plasma β-sitosterol and campesterol concentrations and by a doubling of the calculated apparent cholesterol absorption. These effects partially normalized upon insulin supplementation. Conclusion/interpretation. Our data indicate that effects of insulin-deficiency on bile composition and cholesterol absorption in rats are, at least partly, attributable to changes in hepatic and intestinal Abcg5 and Abcg8 expression. [Diabetologia (2004) Type I diabetes mellitus is associated with specific changes in cholesterol metabolism in humans [1] and in experimental animals [2,3], including increased concentrations of plasma cholesterol, enhanced conversion of cholesterol into bile salts and an enhanced intestinal cholesterol absorption. The hepatobiliary pathway is of crucial importance for the maintenance of cholesterol homeostasis [4]. Bile salts that are secreted by the liver into the intestinal lumen are required for intestinal absorption of dietary cholesterol. The majority of bile salts is subsequently reabsorbed from the intestine and returns to the liver for re-secretion into the bile. The relatively small fraction of bile salts that escapes intestinal absorption is compensated for by de novo synthesis from cholesterol in the liver. Secondly, bile contains considerable amounts of free cholesterol. Since only a part of biliary cholesterol is reabsorbed from the intestine [5], the biliary pathway contributes to a major extent to cholesterol turnover. It is well-established that

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“…The reason suggested by Mi-Hye Lee et al is that the net effect of the complete loss of function of either 'sterolin', two genes transcribed in opposite directions and encoding ABCG5 and ABCG8, results in increased cholesterol and sitosterol absorp- tion, and decreased sitosterol and cholesterol excretion into bile 26) . However, despite having normal plasma cholesterol levels, sitosterolemic patients often develop premature coronary heart disease (CHD), which suggests that high circulating levels of plant sterols per se might be atherogenic, even in non-sitosterolemic subjects.…”

Section: Plant Sterols and Cardiovascular Diseasesmentioning

confidence: 99%

Current Therapy for Patients with Sitosterolemia –Effect of Ezetimibe on Plant Sterol Metabolism

Tsubakio-Yamamoto

Nishida

Nakagawa-Toyama

et al. 2010

JAT

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Sitosterolemia is a rare, autosomal recessive inherited sterol storage disease associated with high tissue and serum plant sterol concentrations, caused by mutations in the adenosine triphosphate-binding cassette (ABC) transporter ABCG5 or ABCG8 genes. Markedly increased serum concentration of plant sterols. such as sitosterol and campesterol, cause premature atherosclerosis and massive xanthomas. Hitherto known treatments for sitosterolemia, including a low-sterol diet, bile-salt binding resins, ileal bypass surgery and low density lipoprotein (LDL) apheresis have not yielded sufficient reduction of serum plant sterol levels and many patients show a sustained elevation of plant sterol levels, subsequently developing premature atherosclerotic cardiovascular diseases. Ezetimibe, an inhibitor of intestinal cholesterol absorption through its binding to Niemann-Pick C1-like 1 (NPC1L1), has been widely used for decreasing serum LDL-cholesterol levels in patients with hypercholesterolemia. Ezetimibe also reduces the gastrointestinal absorption of plant sterols, thereby also lowering the serum concentrations of plant sterols. This pharmacological property of ezetimibe shows its potential as a novel effective therapy for sitosterolemia. In the current review, we discuss the current therapy for patients with sitosterolemia and present two Japanese adolescent patients with this disease, one of whom underwent percutaneous coronary intervention for accelerated coronary atherosclerosis. Ezetimibe administration in addition to conventional drug therapy successfully reduced serum sitosterol levels by 51.3% and 48.9%, respectively, in the two patients, demonstrating ezetimibe as a novel and potent treatment agent for sitosterolemia that could work additively with conventional drug therapy. J Atheroscler Thromb, 2010; 17:891-900.

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Genetic basis of sitosterolemia

Cited by 174 publications

References 31 publications

Phytosterols and phytosterolemia: gene–diet interactions

Phytosterols and phytosterolemia: gene–diet interactions

Down-regulation of hepatic and intestinal Abcg5 and Abcg8 expression associated with altered sterol fluxes in rats with streptozotocin-induced diabetes

Current Therapy for Patients with Sitosterolemia –Effect of Ezetimibe on Plant Sterol Metabolism

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