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Shailendra B. Patel - One of the best experts on this subject based on the ideXlab platform.
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Cryptogenic Cirrhosis and Sitosterolemia: A Treatable Disease If Identified but Fatal If Missed
'Index Copernicus', 2017Co-Authors: Fateh Bazerbachi, Shailendra B. Patel, Erin E. Conboy, Taofic Mounajjed, Kymberly D. Watt, Dusica Babovic-vuksanovic, Patrick S. KamathAbstract:Sitosterolemia is an autosomal recessive metabolic disease caused by mutations in ABCG5 or ABCG8 genes which encode for the (ATP)-binding cassette (ABC) transporters that are responsible for the trafficking of xenosterols. Liver involvement is not a recognized manifestation of this disease, and cirrhosis has been reported only once in the medical literature. We describe a fatal case of a 21-year old South Asian male who presented with decompensated cirrhosis, and biochemical abnormalities consistent with sitostero-lemia. Genetic testing showed a homozygous pathogenic mutation in ABCG5, confirming the diagnosis. Sitosterolemia is a rare, but likely under-recognized condition, and a high degree of suspicion is imperative to make the diagnosis. We propose that Sitosterolemia should be included in the differential diagnosis for patients with cryptogenic cirrhosis, especially as there are effective oral therapies to treat this condition. Newly diagnosed Sitosterolemia patients should undergo a thorough hepatology evaluation and follow-up to evaluate for the presence, development, and progression of any hepatic involvement
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REVIEW Tracking the dietary cholesterol molecule
2016Co-Authors: Shailendra B. Patel, Srividya Kidambi, Curzio Solca, Shailendra PatelAbstract:intestinal cholesterol absorption, NPC1L1, phytosterols, sterolins, sterol trafficking Targeting endogenous cholesterol synthesis has been the focus of many strategies aimed at treating atherosclerosis. With limitations of this approach and the recent discovery of an intestinal cholesterol transporter, Niemann-Pick C1 like 1, and drugs blocking this process such as ezetimibe, the issue of intestinal cholesterol absorption has reached the forefront of lipidology. In addition, two half-transporters (sterolins), encoded by ABCG5 and ABCG8, have been found to be the molecular reasons behind the human disorder of Sitosterolemia. Sterolins seem to play a key role in keeping noncholesterol sterols, such as phytosterols, out of our bodies, and may also be key to cholesterol elimination via biliary secretion in the liver. This review explores the link between dietary cholesterol and atherosclerosis and the rationale behind the current dietary cholesterol recommendations. In addition, potential rate-limiting steps that may control intestinal cholesterol absorption are highlighted wit
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Mapping a gene involved in regulating dietary cholesterol absorption. The Sitosterolemia locus is found at chromosome 2p21
2014Co-Authors: Shailendra B. Patel, Gerald Salen, P O Kwiterovich, Scott M Grundy, Mi-hye Lee, Hideki Hidaka, Anton F H Stalenhoef, Tatu A. Miettinen, Jeffrey S. Rubenstein, Mihael H. PolymeropoulosAbstract:The molecular mechanisms regulating the amount of dietary cholesterol retained in the body as well as the body’s ability to selectively exclude other dietary sterols are poorly understood. Studies of the rare autosomal recessively inherited disease Sitosterolemia (OMIM 210250) may shed some light on these processes. Patients suffering from this disease appear to hyperabsorb both cholesterol and plant sterols from the intestine. Additionally, there is failure of the liver’s ability to preferentially and rapidly excrete these non-cholesterol sterols into bile. Consequently, people who suffer from this disease have very elevated plasma plant sterol levels and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. Identification of this gene defect may therefore thro
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recent advances in understanding the stsl locus and abcg5 abcg8 biology
Current Opinion in Lipidology, 2014Co-Authors: Shailendra B. PatelAbstract:Purpose of reviewTo provide an update on recent advances made in our mechanistic and pathophysiological understanding of the rare human disease Sitosterolemia, the role of ABCG5/ABCG8 in sterol trafficking and how newer data implicate a more wider role in the body.Recent findingsSitosterolemia is ca
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abstract 667 ergosterol or brassicasterol accumulations in abcg8 knockout mice do not account for xenosterol toxicity
Arteriosclerosis Thrombosis and Vascular Biology, 2014Co-Authors: Shailendra B. PatelAbstract:Xenosterol accumulation mice deficient in sterolin function leads to significant toxicity, with infertility, decreased body fat accumulation, macrothrombocytopenia, cardiac fibrosis and premature death1,2. Although sitosterol has been shown to have some biological effect in tissue culture, only stigmasterol has been shown to have a potent biological effect, by activating the transcriptional factor, Lxr3. In patients with Sitosterolemia, feeding shell-fish sterols led to accumulation of shell-fish sterols in their plasma4, suggesting any xenosterol could accumulate, if fed, to mammals deficient in Abcg5 or Abcg8. Fungi do not utilize cholesterol, but instead use ergosterol as the primary membrane sterol. To delineate whether ergosterol could accumulate in Abcg8 knockout mice, and lead to toxicity, we designed a diet that was supplemented with highly enriched ergosterol (>98% purity) and fed this to Abcg8 knockout mice. Over a 12-week period, both male and female Abcg8 knockout mice fed an ergosterol-enrich...
Helen H Hobbs - One of the best experts on this subject based on the ideXlab platform.
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structural role of abcg5 abcg8 in sterol transport
Biophysical Journal, 2017Co-Authors: Jyh-yeuan Lee, Daniel M. Rosenbaum, Helen H HobbsAbstract:ATP binding cassette (ABC) transporters play critical roles in maintaining sterol homeostasis in eukaryotic organisms, including yeast, plants and mammals. In humans, the heterodimeric ABCG5/ABCG8 (G5G8) mediates the excretion of cholesterol and dietary plant sterols into bile and into the gut lumen. Mutations inactivating either ABCG5 or ABCG8 cause Sitosterolemia, a rare autosomal recessive genetic disorder characterized by plant sterol accumulation, hypercholesterolemia, and premature coronary atherosclerosis. ABCG5 and ABCG8 are half ABC transporters;each subunit consists of an N-terminal nucleotide-binding domain (NBD) and a C-terminal transmembrane domain (TMD). The NBDs dimerize to form two catalytically asymmetric nucleotide-binding sites (NBS), one that is catalytically active (NBS2) and the other inactive (NBS1). To understand the structural basis for G5G8-mediated sterol transport we developed a large-scale purification of human G5G8 by exploiting Pichia patoris yeast. We crystallized the transporter in lipid bilayers, solved its structure in a nucleotide-free state at 3.9 A resolution, and generated the first atomic model of an ABC sterol transporter. G5G8 presents a new structural configuration for the TMD of ABC transporters, which is present in a large and functionally diverse ABC2 superfamily. We discover that the TMD and the NBS are coupled through networks of interactions that differ between NBS1 and NBS2, reflecting the catalytic asymmetry of the transporter. A series of conserved polar residues in the TMD form polar networks that we proposed play a role in transmitting signals from the ATPase catalysis in the NBS to sterol transport on the TMD. Molecular dynamic simulation and long-range coevolution analysis revealed an inward-upward TMD movement that predicts a significant conformational change between the TMD subunits. Thus, the G5G8 structure provides a molecular framework that allows us to propose a mechanistic model for ABC transporter-mediated sterol transport and to analyze the disruptive effects of mutations causing Sitosterolemia. The structure will serve as a structural template for homology modelling to a wide range of transport system that is regulated by ABCG transporters and by ABC2 superfamily.
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identification by whole genome resequencing of gene defect responsible for severe hypercholesterolemia
Human Molecular Genetics, 2010Co-Authors: Jonathan J Rios, Jay Shendure, Helen H Hobbs, Evan Stein, Jonathan C CohenAbstract:Whole-genome sequencing is a potentially powerful tool for the diagnosis of genetic diseases. Here, we used sequencing-by-ligation to sequence the genome of an 11-month-old breast-fed girl with xanthomas and very high plasma cholesterol levels (1023 mg/dl). Her parents had normal plasma cholesterol levels and reported no family history of hypercholesterolemia, suggesting either an autosomal recessive disorder or a de novo mutation. Known genetic causes of severe hypercholesterolemia were ruled out by sequencing the responsible genes (LDLRAP, LDLR, PCSK9, APOE and APOB), and Sitosterolemia was ruled out by documenting a normal plasma sitosterol:cholesterol ratio. Sequencing revealed 3 797 207 deviations from the reference sequence, of which 9726 were nonsynonymous single-nucleotide substitutions. A total of 9027 of the nonsynonymous substitutions were present in dbSNP or in 21 additional individuals from whom complete exonic sequences were available. The 699 novel nonsynonymous substitutions were distributed among 604 genes, 23 of which were single-copy genes that each contained 2 nonsynonymous substitutions consistent with an autosomal recessive model. One gene, ABCG5, had two nonsense mutations (Q16X and R446X). This finding indicated that the infant has Sitosterolemia. Thus, whole-genome sequencing led to the diagnosis of a known disease with an atypical presentation. Diagnosis was confirmed by the finding of severe Sitosterolemia in a blood sample obtained after the infant had been weaned. These findings demonstrate that whole-genome (or exome) sequencing can be a valuable aid to diagnose genetic diseases, even in individual patients.
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no association between plasma levels of plant sterols and atherosclerosis in mice and men
Arteriosclerosis Thrombosis and Vascular Biology, 2004Co-Authors: Kenneth R Wilund, Liqing Yu, Jonathan Cohen, Fang Xu, Gloria Lena Vega, Scott M Grundy, Helen H HobbsAbstract:Objective— Sitosterolemia is characterized by elevated plasma levels of plant sterols, hypercholesterolemia and premature coronary heart disease (CHD). CHD develops in some subjects with Sitosterolemia, despite having normal plasma cholesterol levels, suggesting that high circulating levels of plant sterols may be atherogenic. We tested whether elevated plasma levels of plant sterols (sitosterol and campesterol) were associated with atherosclerosis in genetically modified mice and in middle-aged men and women. Methods and Results— Wild-type and hypercholesterolemic female mice with >20-fold higher plasma levels of plant sterols because of inactivation of the ATP-binding cassette (ABC) half transporters G5 and G8 ( G5G8 −/−mice) were fed chow or Western diets for 7 months. No significant differences in aortic lesion area were found when the sitosterolemic mice were compared with littermate controls. To determine whether plasma levels of plant sterols were associated with coronary atherosclerosis in humans, the relationship between plasma plant sterols and coronary calcium (detected by electron beam computer tomography) was examined in 2542 subjects aged 30 to 67 years. Plasma levels of cholesterol, but not sitosterol or campesterol, were significantly higher in subjects with coronary calcium. Conclusions— The results of this study do not support an association between elevated plasma levels of plant sterols and atherosclerosis.
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selective sterol accumulation in abcg5 abcg8 deficient mice
Journal of Lipid Research, 2004Co-Authors: Klaus Von Bergmann, Dieter Lutjohann, Helen H Hobbs, Jonathan CohenAbstract:The ATP binding cassette (ABC) transporters ABCG5 and ABCG8 limit intestinal absorption and promote biliary secretion of neutral sterols. Mutations in either gene cause Sitosterolemia, a rare recessive disease in which plasma and tissue levels of several neutral sterols are in- creased to varying degrees. To determine why patients with Sitosterolemia preferentially accumulate noncholesterol ste- rols, levels of cholesterol and the major plant sterols were compared in plasma, liver, bile, and brain of wild-type and ABCG5/ABCG8-deficient ( G5G8 � / � ) mice. The total sterol content of liver and plasma was similar in G5G8 � / � mice and wild-type animals despite an � 30-fold increase in non- cholesterol sterol levels in the knockout animals. The relative enrichment of each sterol in the plasma and liver of G5G8 � / � mice (stigmasterolsitosterolcholestanolbassicas- terolcampesterolcholesterol) reflected its relative en- richment in the bile of wild-type mice. These results indi- cate that 24-alkylated, � 22 , and 5 � -reduced sterols are preferentially secreted into bile and that preferential biliary secretion of noncholesterol sterols by ABCG5 and ABCG8 prevents the accumulation of these sterols in normal ani- mals. The mRNA levels for 13 enzymes in the cholesterol biosynthetic pathway were reduced in the livers of the G5G8 � / � mice, despite a 50% reduction in hepatic choles- terol level. Thus, the accumulation of sterols other than cholesterol is sensed by the cholesterol regulatory machin- ery. —Yu, L., K. von Bergmann, D. Lutjohann, H. H. Hobbs, and J. C. Cohen. Selective sterol accumulation in ABCG5/ ABCG8-deficient mice. J. Lipid Res. 2004. 45: 301-307.
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Missense mutations in ABCG5 and ABCG8 disrupt heterodimerization and trafficking
Journal of Biological Chemistry, 2004Co-Authors: Gregory A Graf, Jonathan C Cohen, Helen H HobbsAbstract:Mutations in ABCG5 (G5) or ABCG8 (G8) cause Sitosterolemia, an autosomal recessive disease characterized by sterol accumulation and premature atherosclerosis. G5 and G8 are ATP-binding cassette (ABC) half-transporters that must heterodimerize to move to the apical surface of cells. We examined the role of N-linked glycans in the formation of the G5/G8 heterodimer to gain insight into the determinants of folding and trafficking of these proteins. Site-directed mutagenesis revealed that two asparagine residues (Asn(585) and Asn(592)) are glycosylated in G5 and that G8 has a single N-linked glycan attached to Asn(619). N-Linked glycosylation of G8 was required for efficient trafficking of the G5/G8 heterodimer, but mutations that abolished glycosylation of G5 did not prevent trafficking of the heterodimer. Both G5 and G8 are bound by the lectin chaperone, calnexin, suggesting that the calnexin cycle may facilitate folding of the G5/G8 heterodimer. To determine the effects of 13 disease-causing missense mutations in G5 and G8 on formation and trafficking of the G5/G8 heterodimer, mutant forms of the half-transporters were expressed in CHO-K1 cells. All 13 mutations reduced trafficking of the G5/G8 heterodimer from the endoplasmic reticulum to the Golgi complex, and most prevented the formation of stable heterodimers between G5 and G8. We conclude that the majority of the molecular defects in G5 and G8 that cause Sitosterolemia impair transport of the sterol transporter to the cell surface.
Gerald Salen - One of the best experts on this subject based on the ideXlab platform.
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Mapping a gene involved in regulating dietary cholesterol absorption. The Sitosterolemia locus is found at chromosome 2p21
2014Co-Authors: Shailendra B. Patel, Gerald Salen, P O Kwiterovich, Scott M Grundy, Mi-hye Lee, Hideki Hidaka, Anton F H Stalenhoef, Tatu A. Miettinen, Jeffrey S. Rubenstein, Mihael H. PolymeropoulosAbstract:The molecular mechanisms regulating the amount of dietary cholesterol retained in the body as well as the body’s ability to selectively exclude other dietary sterols are poorly understood. Studies of the rare autosomal recessively inherited disease Sitosterolemia (OMIM 210250) may shed some light on these processes. Patients suffering from this disease appear to hyperabsorb both cholesterol and plant sterols from the intestine. Additionally, there is failure of the liver’s ability to preferentially and rapidly excrete these non-cholesterol sterols into bile. Consequently, people who suffer from this disease have very elevated plasma plant sterol levels and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. Identification of this gene defect may therefore thro
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Intestinal Cholesterol Absorption Inhibitor Ezetimibe Added to Cholestyramine for Sitosterolemia and Xanthomatosis
Gastroenterology, 2006Co-Authors: Gerald Salen, Thomas J. Starc, Christine Mccrary Sisk, Shailendra B. PatelAbstract:Sitosterolemia is a rare, recessively inherited disorder characterized by increased absorption and delayed removal of noncholesterol sterols, which is associated with accelerated atherosclerosis, premature coronary artery disease, hemolysis, and xanthomatosis. Treatments include low-sterol diet and bile salt-binding resins; however, these often do not reduce the xanthomatosis. We examined the effects of the intestinal cholesterol/phytosterol transporter inhibitor ezetimibe added to cholestyramine in a young female patient with Sitosterolemia and associated xanthomatosis. The patient was an 11-year-old female with Sitosterolemia presenting with prominent xanthomas in the subcutaneous tissue of both elbows who was receiving treatment with cholestyramine 2 g once daily. Bilateral carotid bruits were audible, and a grade II/VI systolic murmur was detected at the left upper sternal border. She also had a low platelet count of 111,000/μL. Ezetimibe 10 mg once daily was added to the patient's ongoing cholestyramine regimen, and she was evaluated for 1 year. The patient followed an unrestricted diet during the 1-year treatment period. After 1 year of treatment with ezetimibe added to ongoing cholestyramine therapy, the patient's plasma sitosterol and campesterol levels decreased by approximately 50%. Her carotid bruits completely resolved, her systolic murmur diminished, and her platelet count rose to 268,000/μL. More remarkably, the tuberous xanthomas on her elbows had completely regressed. Ezetimibe added to ongoing low-dose cholestyramine therapy led to a marked improvement in plasma sterol concentrations, complete regression of xanthomatosis, resolution of carotid bruits, and improvement in cardiac murmur in a young female patient with Sitosterolemia.
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identification of a gene abcg5 important in the regulation of dietary cholesterol absorption
Nature Genetics, 2001Co-Authors: Mi-hye Lee, Hideki Hidaka, Hideto Kojima, Star Hazard, Sergey Shulenin, Rando Allikmets, Nagahiko Sakuma, R J Pegoraro, Anand Srivastava, Gerald SalenAbstract:The molecular mechanisms regulating the amount of dietary cholesterol retained in the body, as well as the body's ability to exclude selectively other dietary sterols, are poorly understood. An average western diet will contain about 250-500 mg of dietary cholesterol and about 200-400 mg of non-cholesterol sterols. About 50-60% of the dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. Thus, there 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 not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine. The major plant sterol species is sitosterol; hence the name of the disorder. 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. We previously mapped the STSL locus to human chromosome 2p21 and further localized it to a region of less than 2 cM bounded by markers D2S2294 and D2S2291 (M.-H.L. et al., manuscript submitted). We now report that a new member of the ABC transporter family, ABCG5, is mutant in nine unrelated Sitosterolemia patients.
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7-Dehydro-cholesterol down-regulates cholesterol biosynthesis in cultured Smith-Lemli-Opitz syndrome skin fibroblasts
1998Co-Authors: Akira Honda, Lien B Nguyen, Ashok K. Batta, Gerald Salen, Stephen G Tint, Sarah SheferAbstract:Sitosterolemia: diminished activities of acetoacetyl-CoA thiolase, 3-hydroxy-3-methylglutaryl-CoA synthase, reductase, squalene synthase, an
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inverse relationship between plasma cholestanol concentrations and bile acid synthesis in Sitosterolemia
Journal of Lipid Research, 1994Co-Authors: Gerald Salen, Sarah Shefer, G. Stephen Tint, Ashok K. Batta, Gene C NessAbstract:We investigated the relationship between plasma cholestanol (5a-dihydrocholesterol) concentrations and the ac- tivity and mRNA levels of cholesterol 7a-hydroxylase, the rate- controlling enzyme for bile acid synthesis, in three female sitosterolemic homozygotes. In this lipid storage disease, large amounts of plant sterols and cholestanol accumulate because of hyperabsorption and endogenous synthesis, respectively. Plasma cholestanol concentrations were 14 times greater in the three sitosterolemic homozygotes than the mean for five control sub- jects. To investigate the cholestanol biosynthetic pathway, tracer doses of two putative precursors, (1,2-3H)4-cholesten-3-one and (4-14C)7a-hydroxycholesterol were injected intravenously into a homozygote, and radioactivity was sought in cholestanol, bile acids, cholesterol, and sitosterol fractions isolated from plasma and bile. Tritium was concentrated only in cholestanol; neither cholesterol, sitosterol nor bile acids were derived from (1,2-3H)4- cholesten-3-one. In contrast, bile acids were labeled exclusively with I4C from (4-'4C)7a-hydroxycholesterol; no 14C radioac- tivity was detected in cholestanol. Mathematical analysis of specific activity versus time curves for (3H)cholestanol revealed very slow decay, large exchangeable pools, and enhanced synthe- sis in the sitosterolemic homozygote. Measurements of choles- terol 7a-hydroxylase activity were 39% lower in whole liver microsomes from three sitosterolemic homozygotes that con- tained 19% plant sterols as compared to the mean value for six control microsomal specimens that contained 0.1% plant sterols. Removal of the excess plant sterols from the microsomes, in vitro, normalized microsomal cholesterol 7a-hydroxylase ac- tivity in the homozygotes but did not affect enzyme activity in the controls. Equal amounts of cholesterol 7a-hydroxylase mRNA were detected in the livers of both control and sitostero- lemic subjects. Bile acid malabsorption after ileal bypass surgery stimulated cholesterol 7a-hydroxylase activity 78% in sitostero- lemic whole liver microsomes and reduced plasma cholesterol, sitosterol, and cholestanol levels 6l%, 55% and 91%, respec- tively, producing a pronounced decrease in the cholestanolkho- lesterol ratio without changing the sitosterolkholesterol ratio. These results demonstrate that increased cholestanol is synthe- sized from 4-cholesten-3-one and not 7a-hydroxycholesterol in Sitosterolemia. Enhanced pools and plasma concentrations are related inversely to hepatic cholesterol 7a-hydroxylase activity. Competitive inhibition of cholesterol 7a-hydroxylase by the large microsomal plant sterol pool diverts cholesterol into cholestanol. Alternatively, stimulating cholesterol 7a-hydroxylase activity after ileal bypass surgery markedly diminished plasma cholestanol levels. We propose that increased cholestanol is syn- thesized in sitosterolemic subjects because cholesterol 7a- hydroxylase is competitively inhibited by the large microsomal sitosterol pool so that cholesterol that cannot be transformed to bile acids is available as substrate for cholestanol formation. --den, G., A. K. Batta, G. S. Tint, S. Shefer, and G. C. Ness. Inverse relationship between plasma cholestanol concen- trations and bile acid synthesis in Sitosterolemia. J. Lipid Res. 1994. 35: 1a78-1887.
Sarah Shefer - One of the best experts on this subject based on the ideXlab platform.
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A mouse model of Sitosterolemia: absence of Abcg8/sterolin-2 results in failure to secrete biliary cholesterol
BMC Medicine, 2004Co-Authors: Eric Klett, Sarah Shefer, Hongwei Yu, Kangmo Lu, Ashok Batta, Astrid Kosters, Edwin Vink, Michael Altenburg, Jianliang Chen, Richard KleinAbstract:Background Mutations in either of two genes comprising the STSL locus, ATP-binding cassette (ABC)-transporters ABCG5 (encoding sterolin-1) and ABCG8 (encoding sterolin-2), result in Sitosterolemia, a rare autosomal recessive disorder of sterol trafficking characterized by increased plasma plant sterol levels. Based upon the genetics of Sitosterolemia, ABCG5/sterolin-1 and ABCG8/sterolin-2 are hypothesized to function as obligate heterodimers. No phenotypic difference has yet been described in humans with complete defects in either ABCG5 or ABCG8. These proteins, based upon the defects in humans, are responsible for regulating dietary sterol entry and biliary sterol secretion. Methods In order to mimic the human disease, we created, by a targeted disruption, a mouse model of Sitosterolemia resulting in Abcg8/sterolin-2 deficiency alone. Homozygous knockout mice are viable and exhibit Sitosterolemia. Results Mice deficient in Abcg8 have significantly increased plasma and tissue plant sterol levels (sitosterol and campesterol) consistent with Sitosterolemia. Interestingly, Abcg5/sterolin-1 was expressed in both liver and intestine in Abcg8/sterolin-2 deficient mice and continued to show an apical expression. Remarkably, Abcg8 deficient mice had an impaired ability to secrete cholesterol into bile, but still maintained the ability to secrete sitosterol. We also report an intermediate phenotype in the heterozygous Abcg8 +/- mice that are not sitosterolemic, but have a decreased level of biliary sterol secretion relative to wild-type mice. Conclusion These data indicate that Abcg8/sterolin-2 is necessary for biliary sterol secretion and that loss of Abcg8/sterolin-2 has a more profound effect upon biliary cholesterol secretion than sitosterol. Since biliary sitosterol secretion is preserved, although not elevated in the sitosterolemic mice, this observation suggests that mechanisms other than by Abcg8/sterolin-2 may be responsible for its secretion into bile.
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BMC Medicine BioMed Central
2004Co-Authors: Eric Klett, Sarah Shefer, Ashok K. Batta, Astrid Kosters, Edwin Vink, Michael Altenburg, Mi-hye Lee, Jianliang ChenAbstract:Research article A mouse model of Sitosterolemia: absence of Abcg8/sterolin-2 results in failure to secrete biliary cholestero
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Hyperabsorption and retention of campestanol in a sitosterolemic homozygote: comparison with her mother and three control subjects.
Journal of lipid research, 2000Co-Authors: G. Stephen Tint, Ashok K. Batta, Sarah SheferAbstract:We measured the percent absorption, turnover, and distribution of campestanol (24-methyl-5 a -cholestan-3 b - ol) in a sitosterolemic homozygote, her obligate heterozygous mother, and three healthy human control subjects. For rea- sons relating to sterol hyperabsorption, the homozygote con- sumed a diet low in plant sterols that contained campestanol at about 2 mg/day. The heterozygote and three control sub- jects were fed a diet supplemented with a spread that con- tained campestanol at 540 mg/day and sitostanol (24-ethyl- 5 a -cholestan-3 b -ol) at 1.9 g/day as fatty acid esters. Plasma campestanol concentrations determined by capillary gas- liquid chromatography were 0.72 6 0.03 mg/dl in the homozygote, 0.09 6 0.04 mg/dl in the heterozygote, and 0.05 6 0.03 mg/dl for the control mean. After simulta- neous pulse labeling with (3 a - 3 H)campestanol intrave- nously and (23- 14 C)campestanol orally, the maximum per- cent absorption measured by the plasma dual-isotope ratio method as a single time point was 80% in the homozygote, 14.3% in the heterozygote, and 5.5 6 4.3% as the mean for three control subjects. Turnover (pool size) values esti- mated by mathematical analysis of the specific activity ver- sus time (3 a - 3 H)campestanol decay curves were as follows: 261 mg in the homozygote, 27.3 mg in the heterozygote, and 12.8 6 7.6 mg in the three control subjects (homogygote vs. controls, P , 0.001). The calculated production rate (mg/24 h) equivalent to actual absorption in the presence of dietary sterols and stanols was 0.67 mg/day or 31% of in- take in the homozygote, 2.1 mg/day or 0.3% of intake in the heterozygote, and 0.7 6 0.3 mg/day or 0.1% of intake in the three control subjects. However, the excretion constant from pool A (K A ) was prolonged markedly in the homozy- gote, but was 100 times more rapid in the heterozygote and three control subjects. Thus, campestanol, like other non- cholesterol sterols, is hyperabsorbed and retained in sitoster- olemic homozygotes. However, campestanol absorption was only slightly increased in the sitosterolemic heterozygote and removal was as rapid as in control subjects. — Salen, G., G. Xu, G. S. Tint, A. K. Batta, and S. Shefer. Hyperabsorp- tion and retention of campestanol in a sitosterolemic homo- zygote: comparison with her mother and three control sub- jects. J. Lipid Res. 2000. 41: 1883-1889.
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down regulation of cholesterol biosynthesis in Sitosterolemia diminished activities of acetoacetyl coa thiolase 3 hydroxy 3 methylglutaryl coa synthase reductase squalene synthase and 7 dehydrocholesterol delta7 reductase in liver and mononuclear leu
Journal of Lipid Research, 1998Co-Authors: Akira Honda, G. Stephen Tint, Lien B Nguyen, Ashok K. Batta, Sarah SheferAbstract:Sitosterolemia is a recessively inherited disorder characterized by abnormally increased plasma and tissue plant sterol concentrations. Patients have markedly reduced whole body cholesterol biosynthesis associated with sup- pressed hepatic, ileal, and mononuclear leukocyte 3-hydroxy- 3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate- controlling enzyme in cholesterol biosynthetic pathway, coupled with significantly increased low density lipoprotein (LDL) receptor expression. To investigate the mechanism of down- regulated cholesterol biosynthesis, we assayed several other key enzymes in the cholesterol biosynthetic pathway includ- ing acetoacetyl-CoA thiolase, HMG-CoA synthase, squalene synthase, and 7-dehydrocholesterol D 7 -reductase activities in liver and freshly isolated mononuclear leukocytes from four sitosterolemic patients and 19 controls. Hepatic acetoacetyl- CoA thiolase, HMG-CoA synthase, reductase, and squalene synthase activities were significantly decreased ( P , 0.05) 2 39%, 2 54%, 2 76%, and 2 57%, respectively, and 7-dehydro- cholesterol D 7 -reductase activity tended to be lower ( 2 35%) in the sitosterolemic compared with control subjects. The re- duced HMG-CoA synthase, reductase, and squalene synthase activities were also found in mononuclear leukocytes from a sitosterolemic patient. Thus, reduced cholesterol synthesis is caused not only by decreased HMG-CoA reductase but also by the coordinate down-regulation of entire pathway of choles- terol biosynthesis. These results suggest that inadequate cholesterol production in Sitosterolemia is due to abnormal down-regulation of early, intermediate, and late enzymes in the cholesterol biosynthetic pathway rather than a single in- herited defect in the HMG-CoA reductase gene.— Honda, A., G. Salen, L. B. Nguyen, G. S. Tint, A. K. Batta, and S. Shefer. Down-regulation of cholesterol biosynthesis in Sitosterolemia: diminished activities of acetoacetyl-CoA thiolase, 3-hydroxy-3- methylglutaryl-CoA synthase, reductase, squalene synthase, and 7-dehydrocholesterol D 7 -reductase in liver and mononu- clear leukocytes. J. Lipid Res. 1998. 39: 44-50.
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7-Dehydro-cholesterol down-regulates cholesterol biosynthesis in cultured Smith-Lemli-Opitz syndrome skin fibroblasts
1998Co-Authors: Akira Honda, Lien B Nguyen, Ashok K. Batta, Gerald Salen, Stephen G Tint, Sarah SheferAbstract:Sitosterolemia: diminished activities of acetoacetyl-CoA thiolase, 3-hydroxy-3-methylglutaryl-CoA synthase, reductase, squalene synthase, an
Mi-hye Lee - One of the best experts on this subject based on the ideXlab platform.
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Mapping a gene involved in regulating dietary cholesterol absorption. The Sitosterolemia locus is found at chromosome 2p21
2014Co-Authors: Shailendra B. Patel, Gerald Salen, P O Kwiterovich, Scott M Grundy, Mi-hye Lee, Hideki Hidaka, Anton F H Stalenhoef, Tatu A. Miettinen, Jeffrey S. Rubenstein, Mihael H. PolymeropoulosAbstract:The molecular mechanisms regulating the amount of dietary cholesterol retained in the body as well as the body’s ability to selectively exclude other dietary sterols are poorly understood. Studies of the rare autosomal recessively inherited disease Sitosterolemia (OMIM 210250) may shed some light on these processes. Patients suffering from this disease appear to hyperabsorb both cholesterol and plant sterols from the intestine. Additionally, there is failure of the liver’s ability to preferentially and rapidly excrete these non-cholesterol sterols into bile. Consequently, people who suffer from this disease have very elevated plasma plant sterol levels and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. Identification of this gene defect may therefore thro
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BMC Medicine BioMed Central
2004Co-Authors: Eric Klett, Sarah Shefer, Ashok K. Batta, Astrid Kosters, Edwin Vink, Michael Altenburg, Mi-hye Lee, Jianliang ChenAbstract:Research article A mouse model of Sitosterolemia: absence of Abcg8/sterolin-2 results in failure to secrete biliary cholestero
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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
American Journal of Human Genetics, 2001Co-Authors: Mi-hye Lee, Starr Hazard, Angela Brookswilson, Hideki Hidaka, Hideto Kojima, Leiv Ose, Anton F H Stalenhoef, Tatu Mietinnen, Ingemar Bjorkhem, Eric BruckertAbstract: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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identification of a gene abcg5 important in the regulation of dietary cholesterol absorption
Nature Genetics, 2001Co-Authors: Mi-hye Lee, Hideki Hidaka, Hideto Kojima, Star Hazard, Sergey Shulenin, Rando Allikmets, Nagahiko Sakuma, R J Pegoraro, Anand Srivastava, Gerald SalenAbstract:The molecular mechanisms regulating the amount of dietary cholesterol retained in the body, as well as the body's ability to exclude selectively other dietary sterols, are poorly understood. An average western diet will contain about 250-500 mg of dietary cholesterol and about 200-400 mg of non-cholesterol sterols. About 50-60% of the dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. Thus, there 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 not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine. The major plant sterol species is sitosterol; hence the name of the disorder. 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. We previously mapped the STSL locus to human chromosome 2p21 and further localized it to a region of less than 2 cM bounded by markers D2S2294 and D2S2291 (M.-H.L. et al., manuscript submitted). We now report that a new member of the ABC transporter family, ABCG5, is mutant in nine unrelated Sitosterolemia patients.
