β-Sitosterolemia and Xanthomatosis

Bhattacharyya, Ashim K.; Connor, William E.

doi:10.1172/jci107640

Cited by 516 publications

(102 citation statements)

References 33 publications

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“…S itosterolemia is a rare autosomal recessive disorder characterized by the accumulation of plant and animal sterols in blood and tissues (1,2). Affected subjects with this disorder develop large deposits of cholesterol in their skin, tendons, and coronary arteries.…”

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confidence: 99%

“…The pathognomonic feature of sitosterolemia is the elevation in plasma sitosterol, the most abundant plant sterol (1). Sitosterolemic patients also accumulate other sterols in plasma including a variety of plant sterols (campesterol, stigmasterol, and avenasterol) and shellfish sterols (brassicasterol, 24-methylene cholesterol, and 22-dehydrocholesterol) (1,7).…”

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confidence: 99%

“…Sitosterolemic patients also accumulate other sterols in plasma including a variety of plant sterols (campesterol, stigmasterol, and avenasterol) and shellfish sterols (brassicasterol, 24-methylene cholesterol, and 22-dehydrocholesterol) (1,7). In normal individuals these sterols are poorly absorbed and preferentially secreted into the bile (8)(9)(10).…”

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Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion

Hammer

Li-Hawkins

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

648

605

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Cholesterol and other sterols exit the body primarily by secretion into bile. In patients with sitosterolemia, mutations in either of two ATP-binding cassette (ABC) half-transporters, ABCG5 or ABCG8, lead to reduced secretion of sterols into bile, implicating these transporters in this process. To elucidate the roles of ABCG5 and ABCG8 in the trafficking of sterols, we disrupted Abcg5 and Abcg8 in mice (G5G8 ؊/؊ ). The G5G8 ؊/؊ mice had a 2-to 3-fold increase in the fractional absorption of dietary plant sterols, which was associated with an Ϸ30-fold increase in plasma sitosterol. Biliary cholesterol concentrations were extremely low in the G5G8 ؊/؊ mice when compared with wild-type animals (mean ‫؍‬ 0.4 vs. 5.5 mol͞ml) and increased only modestly with cholesterol feeding. Plasma and liver cholesterol levels were reduced by 50% in the chow-fed G5G8 ؊/؊ mice and increased 2.4-and 18-fold, respectively, after cholesterol feeding. These data indicate that ABCG5 and ABCG8 are required for efficient secretion of cholesterol into bile and that disruption of these genes increases dramatically the responsiveness of plasma and hepatic cholesterol levels to changes in dietary cholesterol content.ATP-binding cassette transporters ͉ sitosterolemia ͉ bile ͉ knockout mice S itosterolemia is a rare autosomal recessive disorder characterized by the accumulation of plant and animal sterols in blood and tissues (1, 2). Affected subjects with this disorder develop large deposits of cholesterol in their skin, tendons, and coronary arteries. The accumulation of plant and animal sterols in the blood is caused by an increase in the fractional absorption of sterols from the diet and a decrease in the secretion of sterols into the bile, which is the major route of exit of sterols from the body (3, 4).A striking feature of sitosterolemia is the precipitous fall in plasma cholesterol that follows reductions in dietary cholesterol intake, especially in young patients (5, 6). When normal individuals are switched from a high cholesterol, high fat diet to a low cholesterol, low fat diet, plasma levels of cholesterol fall Ϸ10-20%; in patients with sitosterolemia, plasma cholesterol can fall by Ͼ45% (5, 6). The hypercholesterolemia of sitosterolemia is also sensitive to treatment with bile-acid resins, which stimulate the conversion of cholesterol to bile acids, another pathway for removal of cholesterol from the body.The pathognomonic feature of sitosterolemia is the elevation in plasma sitosterol, the most abundant plant sterol (1). Sitosterolemic patients also accumulate other sterols in plasma including a variety of plant sterols (campesterol, stigmasterol, and avenasterol) and shellfish sterols (brassicasterol, 24-methylene cholesterol, and 22-dehydrocholesterol) (1, 7). In normal individuals these sterols are poorly absorbed and preferentially secreted into the bile (8-10). These sterols comprise only Ϸ1% of plasma and tissue sterols in normal individuals but Ϸ15% of circulating and tissue sterols in sitosterolemia (11).Studies of sitoste...

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Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion

Hammer

Li-Hawkins

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

648

605

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“…Sitosterolemia is a relatively rare autosomal recessive disorder characterized by the accumulation of plant sterols in blood and tissues. Patients frequently develop tendon and cutaneous xanthomas and, most important, are at risk of developing premature coronary atherosclerosis (11)(12)(13)(14). A number of associated features, including hemolysis, abnormal platelets, and iron deficiency, have occasionally been reported (12,15,16).…”

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Plant Sterols Cause Macrothrombocytopenia in a Mouse Model of Sitosterolemia

Kruit

Drayer

Bloks

et al. 2008

Journal of Biological Chemistry

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Mutations in either ABCG5 or ABCG8 cause sitosterolemia, an inborn error of metabolism characterized by high plasma plant sterol concentrations. Recently, macrothrombocytopenia was described in a number of sitosterolemia patients, linking hematological dysfunction to disturbed sterol metabolism. Here, we demonstrate that macrothrombocytopenia is an intrinsic feature of murine sitosterolemia. Abcg5-deficient (Abcg5 ؊/؊ ) mice showed a 68% reduction in platelet count, and platelets were enlarged compared with wild-type controls. Macrothrombocytopenia was not due to decreased numbers of megakaryocytes or their progenitors, but defective megakaryocyte development with deterioration of the demarcation membrane system was evident. Lethally irradiated wild-type mice transplanted with bone marrow from Abcg5 ؊/؊ mice displayed normal platelets, whereas Abcg5 ؊/؊ mice transplanted with wild-type bone marrow still showed macrothrombocytopenia. Treatment with the sterol absorption inhibitor ezetimibe rapidly reversed macrothrombocytopenia in Abcg5 ؊/؊ mice concomitant with a strong decrease in plasma plant sterols. Thus, accumulation of plant sterols is responsible for development of macrothrombocytopenia in sitosterolemia, and blocking intestinal plant sterol absorption provides an effective means of treatment.Plant sterols structurally differ from cholesterol only by the presence of an additional methyl or ethyl group at C-24 (campesterol and sitosterol, respectively), in some cases with an additional double bond at C-22 (brassicasterol and stigmasterol, respectively). These structural differences appear to have a major impact on their handling in the body. Despite the fact that regular Western diets contain similar amounts of cholesterol and plant sterols (intakes of ϳ200 -400 mg/day for both) (1), plasma levels of plant sterols are Ͼ100 times lower than those of cholesterol in healthy individuals (2), indicating the presence of effective systems to prevent plant sterol accumulation in the human body. It has become clear that the ATPbinding cassette half-transporters ABCG5 and ABCG8, most abundantly present in intestine and liver, are critically involved herein. ABCG5 and ABCG8 function as an obligate heterodimer and mediate cholesterol and plant sterol transport out of intestinal and hepatic cells (3, 4). The functional heterodimer is present at the apical membranes of enterocytes and hepatocytes, where it transports (plant) sterols back into the intestinal lumen or bile, respectively (4, 5). Expression of ABCG5 and ABCG8 in other organs and tissues is relatively low (6 -8), and functionality at sites other than intestine and liver has not been reported.Mutations in either the ABCG5 or ABCG8 gene cause sitosterolemia (9, 10). Sitosterolemia is a relatively rare autosomal recessive disorder characterized by the accumulation of plant sterols in blood and tissues. Patients frequently develop tendon and cutaneous xanthomas and, most important, are at risk of developing premature coronary atherosclerosis (11)(12)(13)(14). A ...

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“…The ATPbinding cassette (ABC) 1 half-transporters ABCG5 and ABCG8 (ABCG5/G8) have been recently identified as the genes defective in sitosterolemia (10 -12). The increased plasma and tissue levels of animal and plant sterols found in sitosterolemic patients have been attributed to enhanced absorption and decreased biliary excretion (1-4, 6, 8, 13-16).…”

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Hepatic ABCG5 and ABCG8 Overexpression Increases Hepatobiliary Sterol Transport but Does Not Alter Aortic Atherosclerosis in Transgenic Mice

Basso

Shamburek

et al. 2004

Journal of Biological Chemistry

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The individual roles of hepatic versus intestinal ABCG5 and ABCG8 in sterol transport have not yet been investigated. To determine the specific contribution of liver ABCG5/G8 to sterol transport and atherosclerosis, we generated transgenic mice that overexpress human ABCG5 and ABCG8 in the liver but not intestine (liver G5/G8-Tg) in three different genetic backgrounds: C57Bl/6, apoE-KO, and low density lipoprotein receptor (LDLr)-KO. Hepatic overexpression of ABCG5/G8 enhanced hepatobiliary secretion of cholesterol and plant sterols by 1.5-2-fold, increased the amount of intestinal cholesterol available for absorption and fecal excretion by up to 27%, and decreased the accumulation of plant sterols in plasma by ϳ25%. However, it did not alter fractional intestinal cholesterol absorption, fecal neutral sterol excretion, hepatic cholesterol concentrations, or hepatic cholesterol synthesis. Consequently, overexpression of ABCG5/G8 in only the liver had no effect on the plasma lipid profile, including cholesterol, HDL-C, and non-HDL-C, or on the development of proximal aortic atherosclerosis in C57Bl/6, apoE-KO, or LDLr-KO mice. Thus, liver ABCG5/G8 facilitate the secretion of liver sterols into bile and serve as an alternative mechanism, independent of intestinal ABCG5/G8, to protect against the accumulation of dietary plant sterols in plasma. However, in the absence of changes in fractional intestinal cholesterol absorption, increased secretion of sterols into bile induced by hepatic overexpression of ABCG5/G8 was not sufficient to alter hepatic cholesterol balance, enhance cholesterol removal from the body or to alter atherogenic risk in liver G5/G8-Tg mice. These findings demonstrate that overexpression of ABCG5/G8 in the liver profoundly alters hepatic but not intestinal sterol transport, identifying distinct roles for liver and intestinal ABCG5/G8 in modulating sterol metabolism.Sitosterolemia, also known as phytosterolemia (1-9) is a rare genetic disorder characterized by elevated plasma and tissue levels of plant, shellfish, and animal sterols and the development of tendon and tuberous xanthomas, hemolytic episodes, arthritis, and premature coronary artery disease. The ATPbinding cassette (ABC) 1 half-transporters ABCG5 and ABCG8 (ABCG5/G8) have been recently identified as the genes defective in sitosterolemia (10 -12). The increased plasma and tissue levels of animal and plant sterols found in sitosterolemic patients have been attributed to enhanced absorption and decreased biliary excretion (1-4, 6, 8, 13-16). Unlike cholesterol, sitosterol accumulation does not inhibit HMGCoA reductase activity in human monocyte-derived macrophages (17). The inadequate down-regulation of HMGCoA reductase activity by plant sterols may promote foam cell formation and explain, in part, the increased risk of atherosclerosis in sitosterolemia (17).Several lines of evidence implicate ABCG5/G8 in intestinal and biliary sterol transport. First, ABCG5/G8 are expressed in the liver and small intestine and, to a lesser degree, in th...

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β-Sitosterolemia and Xanthomatosis

Cited by 516 publications

References 33 publications

Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion

Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion

Plant Sterols Cause Macrothrombocytopenia in a Mouse Model of Sitosterolemia

Hepatic ABCG5 and ABCG8 Overexpression Increases Hepatobiliary Sterol Transport but Does Not Alter Aortic Atherosclerosis in Transgenic Mice

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