Unexpected failure of bile acid malabsorption to stimulate cholesterol synthesis in sitosterolemia with xanthomatosis. Comparison with lovastatin.

Nguyen, Lien; Salen, Gerald; Shefer, Sarah; Shore, Virgie G.; Tint, G. Stephen; Ness, Gene C.

doi:10.1161/01.atv.10.2.289

Cited by 34 publications

(24 citation statements)

References 24 publications

(13 reference statements)

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“…Finally, bile acid malabsorption induced either by treatment with sequestering resins (cholestyramine and colestipol) or by ileal bypass surgery lowers plasma sterol (cholesterol and sitosterol) concen-trations by 25-50%. 33 The decrease in plasma sterol concentrations is greater than expected and is not associated with the anticipated upregulation of cholesterol synthesis and HMG-CoA reductase activity that is usually noted in mononuclear cells from subjects treated with cholestyramine. 33 Importantly, clinical symptoms (xanthomas, aortic systolic murmurs, and arthritis) improved in one patient as plasma sterol concentrations declined, without the expected stimulation of cholesterol synthesis.…”

Section: Sitosterol Turnovermentioning

confidence: 80%

Increased sitosterol absorption is offset by rapid elimination to prevent accumulation in heterozygotes with sitosterolemia.

Salen

Tint

Shefer

et al. 1992

Arterioscler Thromb

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Using plasma isotope-kinetic methods, we measured the absorption and turnover rates of cholesterol and sitosterol (24-ethylcholesterol) in two obligate heterozygotes (parents) and their homozygous daughter with sitosterolemia with xanthomatosis. Diets contained approximately 500 mg/day cholesterol and 100 mg/day sitosterol. In the homozygote, plasma cholesterol and apolipoprotein B concentrations were slightly higher, but sitosterol levels were 22 and 58 times higher than in her heterozygous parents. Cholesterol absorption was at the high end of the normal range in both heterozygotes (59% and 84%) and in the homozygote (62%) (value in the control subject 48%). In contrast, cholesterol synthesis was severely depressed in the homozygote (28% and 26% as great as in the heterozygotes and the control, respectively). Sitosterol absorption in the homozygote (34%) was 12 and 2.0 times greater than in the heterozygotes and 6.8 times greater than in the control. The sitosterol turnover rate, calculated independently by mathematical analysis of specific-activity decay curves, amounted to 15 and 24 mg/day in the heterozygotes compared with 27 mg/day in the homozygote and 7.9±2J mg/day in five control subjects. However, the total body sitosterol pool was 15 and 103 times larger in the homozygote (4,080 mg) than in her heterozygous parents because of extremely slow removal. The average sitosterol elimination constant in the heterozygotes (K A =0.11 day" 1 ) was 10 times that in the homozygote (K A =0.01 day" 1 ) but 35% less than that in the controls (K A =0.17 day" 1 ). These results demonstrate that despite enhanced sitosterol absorption, small body pools and low plasma concentrations result from rapid elimination associated with adequate cholesterol synthesis in sitosterolemic heterozygotes. In distinction, sitosterol accumulates and body pools are disproportionately enlarged because increased absorption is combined with decreased removal, which may compensate for reduced cholesterol synthesis in sitosterolemic homozygotes. S itosterolemia with xanthomatosis is a rare lipid storage disease that presents clinically with accelerated atherosclerosis, tendon and tuberous xanthomas, hemotysis, and symmetrical arthritis and arthralgias involving the ankle and knee joints.1 Increased amounts of plant sterols (sitosterol, campesterol, and stigmasterol) and 5a-stanols (cholestanol, 5a-sitostanol, and 5a-campestanol) are present in plasma and all tissues except brain.2 Enhanced absorption of sitosterol and structurally related sterols has been suggested to account for the enlarged pools, 3 -7 while cholestanol and 5o-saturated plant sterol derivatives are produced endogenousry because diets are virtually devoid of these stanols. 8 - 10 The disease isFrom the Veterans Administration Medical Center, East Orange, and the University of Medicine and Dentistry-New Jersey Medical College, Newark, NJ.Supported by Research Service, Veterans Administration, and US Public Health Service grants HL-17818, DK-18707, and DK-26756.Address for c...

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Section: Sitosterol Turnovermentioning

confidence: 80%

Increased sitosterol absorption is offset by rapid elimination to prevent accumulation in heterozygotes with sitosterolemia.

Salen

Tint

Shefer

et al. 1992

Arterioscler Thromb

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“…For controls, values from 20 healthy subjects are given and show that cholesterol normally represents 99.6% of the total sterols with about 0.2% cholestanol and 0.2% plant sterols. In some heterozygotes, cholestanol and sitosterol levels are similar to controls (31,32,37). However, in several obligate heterozygotes, cholestanol and sitosterol levels were slightly but significantly higher than the control means, but still substantially less than those found in their homozygous offsprings (17,52).…”

Section: Figmentioning

confidence: 82%

Sitosterolemia

Salen

and

Batta

2002

Cardiovascular Drug Reviews

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Sitosterolemia was first described 28 years ago in two sisters. They had tendon xanthomas, normal plasma cholesterol levels, and elevated plant sterol levels. The high plant sterol levels were shown to be due to the increased absorption and delayed removal of plant sterols from the body. The increased absorption of plant sterols does not affect cholesterol absorption in these patients. However, cholesterol biosynthesis pathway is downregulated and turnover rates are reduced. Bile acid binding resins and ileal bypass surgery are effective treatments for sitosterolemic patients, whereas statins are ineffective. Sitosterolemia is inherited as a recessive trait. Recent studies have shown that mutations in ABCG5 and ABCG8 genes contribute to sitosterolemia. Most likely, ABCG5 and ABCG8 proteins function as obligate heterodimers and play a role in the absorption of plant sterol or control their rate of absorption.

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“…Reduction of the plasma sterol concentrations was associated with clinical improvement, including the disappearance of aortic systolic murmurs. The observations that cholesterol synthesis and microsomal HMG-CoA reductase activity were not stimulated in mononuclear leukocytes isolated from sitosterolemia patients after ileal bypass surgery or cholestyramine treatment have been interpreted as supporting the hypothesis of an inherent defect in cholesterol synthesis in patients with sitosterolemia 39,40) .…”

Section: Surgical Therapy (Partial Ileal Bypass Surgery)mentioning

confidence: 87%

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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Unexpected failure of bile acid malabsorption to stimulate cholesterol synthesis in sitosterolemia with xanthomatosis. Comparison with lovastatin.

Cited by 34 publications

References 24 publications

Increased sitosterol absorption is offset by rapid elimination to prevent accumulation in heterozygotes with sitosterolemia.

Increased sitosterol absorption is offset by rapid elimination to prevent accumulation in heterozygotes with sitosterolemia.

Sitosterolemia

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

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