Postprandial Lipoprotein Metabolism in Familial Hypobetalipoproteinemia

Hooper, Amanda J.; Robertson, Ken; Barrett, P. Hugh R.; Parhofer, Klaus G.; Bockxmeer, Frank M. van; Burnett, John R.

doi:10.1210/jc.2006-1998

Cited by 28 publications

(15 citation statements)

References 21 publications

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“…Whole-body in vivo turnover studies, however, returned convincing evidence that the elevated LDL-C in these two siblings was not attributable to increased de novo cholesterol synthesis but, rather, to impaired LDL catabolism. This conclusion was subsequently substantiated by 125 I-LDL turnover studies and a biodistribution and uptake analysis of 99m technetium-labeled LDL in three Sardinian ARH patients ( 309 ). Thus, these patients had a marked reduction in the fractional catabolic rate of LDL (patients versus fi ve controls: 0.19 ± 0.1 and 0.36 ± 0.03 pools/day, P < 0.001), plus a signifi cant increase in LDL production (20.7 ± 4.4 versus 14.0 ± 2.4 mg/kg/day, P < 0.01), although this increase is lower than that typically seen in homozygous ADH-1 patients.…”

Section: Recruiting Ldl:ldlr Into Clathrin-coated Structures For Intementioning

confidence: 75%

“…The parents did not clinically manifest fat malabsorption. However, when Hooper et al ( 125 ) formally tested the postprandial fat responses of other similarly asymptomatic, heterozygote, FHBL subjects (apoB100/apoB6.9, n = 3; apoB100/apoB25.8, n = 1; apoB100/apoB40.3, n = 2), their plasma triglyceride and apoB-48 levels peaked earlier than in the controls (n = 10), and these peaks were markedly reduced in magnitude. Thus, these fi ndings support the anecdotal reports of intestinal manifestations suggestive of mild fat malabsorption in apoB100/apoB6.7 ( 126 ) and apoB100/B8.2 ( 127 ) individuals, when they refrained from their fat-restricted diet.…”

Section: Apob-specifi C Fhbl Clinically Fhbl ([Omim #107730]mentioning

confidence: 99%

“…An early study involving 9 patients with clinical features of this condition and 50 controls ( 162 ) revealed that the patients had increased concentrations of both plasma apoE (44.8 ± 8.2 g/ml versus 36.3 ± 11.1 g/ml, P < 0.025) and an apoE cholesterolenriched HDL subfraction ( ‫ف‬ 1.5-fold) that had the capacity to compete with 125 I-LDL for specifi c binding sites on the surface of cultured human skin fi broblasts. However, the apoE genotype status of these patients was not determined ( Fig.…”

Section: Update On the Role Of Mtp Function In Cholesterol Homeostasismentioning

confidence: 99%

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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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Section: Recruiting Ldl:ldlr Into Clathrin-coated Structures For Intementioning

confidence: 75%

Section: Apob-specifi C Fhbl Clinically Fhbl ([Omim #107730]mentioning

confidence: 99%

Section: Update On the Role Of Mtp Function In Cholesterol Homeostasismentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

show abstract

“…They compared fat absorption between patients with heterozygous FHBL with apoB <48 and apoB >48 and found no difference between them suggesting that one allele of intestinal apoB-48 is sufficient for normal fat absorption. Hooper et al (2007) performed OFTT and detected postprandial apoB-48 kinetics in patients with heterozygous FHBL (apoB-6.9, apoB-25.8, and apoB-40.3). As a result, these patients with heterozygous FHBL, caused by truncations shorter than apoB-48, showed a lower production and normal clearance of triglyceride-rich lipoproteins.…”

Section: Discussionmentioning

confidence: 99%

Extreme Contrast of Postprandial Remnant-Like Particles Formed in Abetalipoproteinemia and Homozygous Familial Hypobetalipoproteinemia

et al. 2015

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Background: Familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL) are rare inherited forms of hypolipidemia. Their differential diagnosis is important for predicting of the prognosis and selecting appropriate therapy.Materials and Methods: Genetic analysis was performed in two patients with primary hypocholesterolemia born from consanguineous parents. The oral fat tolerance test (OFTT) was performed in one patient with FHBL (apoB-87.77) and one with ABL as well as in four normal control subjects. After overnight fasting, blood samples were drawn. Serum lipoprotein and remnant-like particle (RLP) fractions were determined by HPLC analysis.Results: Both patients with homozygous FHBL were asymptomatic probably because of preserved levels of fatsoluble vitamins, especially vitamin E. The patients with FHBL were homozygous because of novel apoB-83.52 and apoB-87.77 mutations, and although one of them (apoB-87.77) had fatty liver disease, microscopic findings suggesting nonalcoholic steatohepatitis were absent. Fasting apoB-48 and RLP-triglyceride levels in the patient with homozygous FHBL, which were similar to those in normal control subjects, increased after OFTT both in normal control subjects and the patient with FHBL but not in the patient with ABL, suggesting that the fat load administered was absorbed only in the patient with FHBL.Conclusion: Although lipid levels in the patients with homozygous FHBL and ABL were comparable, fasting, postoral fat loading of apoB-48, as well as RLP-triglyceride

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“…This implies that FHBL heterozygotes with truncated ApoBs shorter than ApoB-48 have a reduced capacity of CM production and may manifest intestinal lipid malabsorption, having only one functional ApoB-48 allele [24,27].…”

Section: Molecular Genetics Of Fhbl Fhbl Due To Mutations In Apob Genementioning

confidence: 99%

Genetics of familial hypobetalipoproteinemia

Tarugi¹,

Averna²

2007

Future Lipidology

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Primary hypobetalipoproteinemias include three monogenic disorders: the relatively frequent codominant familial hypobetalipoproteinemia (FHBL), the rare recessive conditions abetalipoproteinemia (ABL) and chylomicron retention disease (CMRD). Approximately 50% of FHBL patients are carriers of mutations in the APOB gene, mostly causing the formation of truncated forms of ApoB. In some kindred, FHBL is linked to a locus on chromosome 3 (3p21), but the candidate gene is still unknown. Recently, a FHBL-like phenotype was observed in carriers of mutations of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene causing loss-of-function of the encoded protein, a proprotein convertase that regulates LDL-receptor number in the liver. Inactivation of the PCSK9 protein is associated with an increased number of LDL receptors and increased receptor-mediated hepatic uptake of plasma LDL. ABL and CMRD are due to mutations in the microsomal triglyceride transfer protein and Sar1-ADP-ribosylation GTPase 2 genes, which affect assembly and secretion of ApoB-containing lipoproteins. In this review we present the current information on the genetics and pathophysiology of these disorders affecting either the secretion or the catabolism of ApoB-containing lipoproteins

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Postprandial Lipoprotein Metabolism in Familial Hypobetalipoproteinemia

Abstract: We have demonstrated that heterozygous FHBL subjects with apoB truncations shorter than apoB-48, and therefore only a single fully-functional apoB-48 allele, have decreased TRL production but normal postprandial TRL particle clearance.

Cited by 28 publications

References 21 publications

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

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

Extreme Contrast of Postprandial Remnant-Like Particles Formed in Abetalipoproteinemia and Homozygous Familial Hypobetalipoproteinemia

Genetics of familial hypobetalipoproteinemia

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