Phenotypic heterogeneity of sitosterolemia

Wang, Jian; Joy, Tisha; Mymin, David; Fröhlich, Jiří; Hegele, Robert A.

doi:10.1194/jlr.m400310-jlr200

Cited by 82 publications

(56 citation statements)

References 44 publications

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“…The accumulation of sterols in the blood is a consequence of both intestinal hyperabsorption and reduced biliary excretion (239). Hitherto, six mutations in ABCG5 and nine mutations in ABCG8 genes have been identified in patents with sitosterolemia (29,204,220,398). Graf et al (110) have demonstrated that most disease-causing missense mutations prevent the formation of stable ABCG5/ABCG8 heterodimers and result in impaired trafficking from the endoplasmic reticulum to the cell surface.…”

Section: Physiological Function and Clinical Relevance Of Abcg5/abcg8mentioning

confidence: 99%

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

Sarkadi¹,

Homolya²,

Szakács³

et al. 2006

Physiological Reviews

642

543

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In this review we give an overview of the physiological functions of a group of ATP binding cassette (ABC) transporter proteins, which were discovered, and still referred to, as multidrug resistance (MDR) transporters. Although they indeed play an important role in cancer drug resistance, their major physiological function is to provide general protection against hydrophobic xenobiotics. With a highly conserved structure, membrane topology, and mechanism of action, these essential transporters are preserved throughout all living systems, from bacteria to human. We describe the general structural and mechanistic features of the human MDR-ABC transporters and introduce some of the basic methods that can be applied for the analysis of their expression, function, regulation, and modulation. We treat in detail the biochemistry, cell biology, and physiology of the ABCB1 (MDR1/P-glycoprotein) and the ABCG2 (MXR/BCRP) proteins and describe emerging information related to additional ABCB- and ABCG-type transporters with a potential role in drug and xenobiotic resistance. Throughout this review we demonstrate and emphasize the general network characteristics of the MDR-ABC transporters, functioning at the cellular and physiological tissue barriers. In addition, we suggest that multidrug transporters are essential parts of an innate defense system, the “chemoimmunity” network, which has a number of features reminiscent of classical immunology.

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Section: Physiological Function and Clinical Relevance Of Abcg5/abcg8mentioning

confidence: 99%

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

Sarkadi¹,

Homolya²,

Szakács³

et al. 2006

Physiological Reviews

642

543

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“…Clinically, sitosterolemia (also known as phytosterolemia) manifests either in children as tendon and tuberous xanthomas (67)(68)(69)(70)(71) or in young adults with severe CHD attributable to massive accumulation of sterols and stanols in monocyte-derived macrophages ( 25,68,(72)(73)(74)(75). Other clinical manifestations include arthralgia and intermittent arthritis ascribed to sitosterol deposits ( 45,70 ); liver disease ( 45 ); and hematological abnormalities ( 45,69,76,77 ), including abnormally shaped, fragile erythrocytes and large platelets.…”

Section: Abcg5/8 Geneticsmentioning

confidence: 99%

Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk

Calandra

Tarugi

Speedy

et al. 2011

Journal of Lipid Research

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This review covers the dietary and biochemical origins and fates of key classes of sterol molecules in humans, namely, cholesterol and the relatively under-recognized and often unappreciated noncholesterol sterols and stanols; the intra-and intercellular systems that govern their transport; and the contribution of innate genetic programs to the biochemically observed levels of plasma LDL-cholesterol (LDL-C). The reasons for these foci are both biological and medical. The former is the burgeoning knowledge of the normal physiological roles that cholesterol performs within cell membranes in supporting receptor-mediated signaling activities ( 1-4 ), the movement of diverse molecules through different membranebound compartments (5)(6)(7)(8), and multiple other cell functions (9)(10)(11), including myelination ( 12 ). The latter, Abstract This review integrates historical biochemical and modern genetic fi ndings that underpin our understanding of the low-density lipoprotein (LDL) dyslipidemias that bear on human disease. These range from life-threatening conditions of infancy through severe coronary heart disease of young adulthood, to indolent disorders of middle-and oldage. We particularly focus on the biological aspects of those gene mutations and variants that impact on sterol absorption and hepatobiliary excretion via specifi c membrane transporter systems ( NPC1L1 , ABCG5/8 ); the incorporation of dietary sterols ( MTP ) and of de novo synthesized lipids ( HMGCR, TRIB1 ) into apoB-containing lipoproteins ( APOB ) and their release into the circulation ( ANGPTL3, SARA2, SORT1 ); and receptor-mediated uptake of LDL and of intestinal and hepatic-derived lipoprotein remnants ( LDLR, APOB, APOE, LDLRAP1, PCSK9, IDOL ).The insights gained from integrating the wealth of genetic data with biological processes have important implications for the classifi cation of clinical and presymptomatic diagnoses of traditional LDL dyslipidemias, sitosterolemia, and newly emerging phenotypes, as well as their management through both nutritional and pharmaceutical means. -Calandra, S., P. Tarugi Abbreviations: ABCG5, ATP-binding cassette, subfamily G, member 5; ABCG8, ATP-binding cassette, subfamily G, member 8; ABL, abetalipoproteinemia; ADH, autosomal dominant hypercholesterolemia; ANGPTL3, angiopoietin-like 3; ARH, autosomal recessive hypercholesterolemia; BMI, body mass index; CAC, coronary artery calcifi cation; CAD, coronary artery disease; CHD, coronary heart disease; CMRD, chylomicron retention disease; CYP7A1 , cholesterol 7 ␣ -hydroxylase; EGF, epidermal growth factor; ER, endoplasmic reticulum; FCHL, familial combined hyperlipidemia; FDB, familial defective apoB; FH, familial hypercholesterolemia; FHBL, familial hypobetalipoproteinemia; GWAS, genome-wide association study; HMGCR, HMGCoA reductase; IDOL, inducible degrader of LDLR; LD, linkage disequilibrium; LDL-C, LDL-cholesterol; LDLR, LDL receptor; LRP1, LDLRAP1, LDLR-associated protein 1; LDLR-related protein 1; LXR, liver X receptor; MI, myocardial infarction; MTP, m...

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“…Outros formas raras de ARH incluem sitosterolemia ou fitosterolemia, em razão de mutações em dois genes adjacentes e com orientações opostas (ABCG5 e ABCG8) que codificam proteínas transportadoras da família ABC (ATP binding cassete) denominadas esterolina-1 e esterolina-2 57 ; deficiência de colesterol 7-alfa hidroxilase (CYP7A1), que é a enzima da primeira etapa na síntese de ácidos biliares, resultando em colesterol intra-hepático aumentado e expressão reduzida de receptores de LDL na superfície do hepatócito. A deficiência de CYP7A1 é a menos comum das condições autossômicas recessivas que podem causar graves hipercolesterolemias 56 .…”

Section: Diretriz Brasileira De Hipercolesterolemia Familiar (Hf)unclassified

I Diretriz Brasileira de Hipercolesterolemia Familiar (HF)

Pereira¹,

Gagliardi²,

Lottenberg³

et al. 2012

Arquivos Brasileiros De Cardiologia

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Phenotypic heterogeneity of sitosterolemia

Cited by 82 publications

References 44 publications

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System

Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk

I Diretriz Brasileira de Hipercolesterolemia Familiar (HF)

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