Defects of Bile Acid Synthesis in Zellweger's Syndrome

Hanson, Russell F.; Szczepanik-Vanleeuwen, Patricia A.; Williams, Gale C.; Grabowski, Gregory A.; Sharp, Harvey L.

doi:10.1126/science.424737

Cited by 173 publications

(70 citation statements)

References 8 publications

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“…In addition, C 27 BAs such as di-and tetrahydroxycholestanoic acid were changed significantly in liver samples but not in cecal samples (Figure 4d). Accumulated levels of C 27 BAs were already described in patients with mitochondrial dysfunction in Zellweger's syndrome (Hanson et al, 1979). Here all FAs were increased in the liver of C57N mice (Figure 4f).…”

Section: Bacterial-derived Metabolitesmentioning

confidence: 54%

Distinct signatures of host–microbial meta-metabolome and gut microbiome in two C57BL/6 strains under high-fat diet

et al. 2014

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A combinatory approach using metabolomics and gut microbiome analysis techniques was performed to unravel the nature and specificity of metabolic profiles related to gut ecology in obesity. This study focused on gut and liver metabolomics of two different mouse strains, the C57BL/6J (C57J) and the C57BL/6N (C57N) fed with high-fat diet (HFD) for 3 weeks, causing dietinduced obesity in C57N, but not in C57J mice. Furthermore, a 16S-ribosomal RNA comparative sequence analysis using 454 pyrosequencing detected significant differences between the microbiome of the two strains on phylum level for Firmicutes, Deferribacteres and Proteobacteria that propose an essential role of the microbiome in obesity susceptibility. Gut microbial and liver metabolomics were followed by a combinatory approach using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) and ultra performance liquid chromatography time of tlight MS/MS with subsequent multivariate statistical analysis, revealing distinctive host and microbial metabolome patterns between the C57J and the C57N strain. Many taurine-conjugated bile acids (TBAs) were significantly elevated in the cecum and decreased in liver samples from the C57J phenotype likely displaying different energy utilization behavior by the bacterial community and the host. Furthermore, several metabolite groups could specifically be associated with the C57N phenotype involving fatty acids, eicosanoids and urobilinoids. The mass differences based metabolite network approach enabled to extend the range of known metabolites to important bile acids (BAs) and novel taurine conjugates specific for both strains. In summary, our study showed clear alterations of the metabolome in the gastrointestinal tract and liver within a HFD-induced obesity mouse model in relation to the host-microbial nutritional adaptation.

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Section: Bacterial-derived Metabolitesmentioning

confidence: 54%

Distinct signatures of host–microbial meta-metabolome and gut microbiome in two C57BL/6 strains under high-fat diet

et al. 2014

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“…In conclusion, the accumulation of odd-numbered DA and 2-hydroxy-sebacic acid in ZS and NALD, together with increased plasma levels of VLCFA (5-8), phytanic acid (9), and pipecolic acid (27), as well as the impairment of bile acids (28) and plasmalogens (29-31) synthesis, may be an additional useful markers in this group of peroxisomal disorders.…”

Section: Analysis and Quantitation Of Urinary Organic Acidsmentioning

confidence: 99%

Medium- and Long-Chain Dicarboxylic Aciduria in Patients with Zellweger Syndrome and Neonatal Adrenoleukodystrophy

1986

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ABSTRACT. This study reports that patients with neonatal adrenoleukodystrophy andIn rat liver, 6-oxidation of both VLCFA (1-3) and DA (4) occurs mostly in peroxisomes, only a minor fraction of these substrates being oxidized in mitochondria (3, 4).The accumulation of VLCFA in brain, adrenal glands, fibroblasts, and plasma of patients with ZS and NALD (5-8) have been attributed to a blockade of the peroxisomal oxidation of these fatty acids (3). We report here that odd-and even-numbered DA are excreted in excess in the urine of patients with ZS or NALD, which suggests that the peroxisomal and/or mitochondria1 P-oxidation of DA is also impaired.

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“…Increased amounts of C27-bile acid intermediates have been detected in bile, serum, and urine of the patients (3)(4)(5)(6). These intermediates include 3a,7a,dihydroxy-5(3-cholestan-26-oic acid (DHCA),' 3a,7a, 1 2a-trihydroxy-5/3-cholestan-26-oic acid (THCA), and 3a,7a, 12a,24-tetrahydroxy-5f3-cholestan-26-oic acid (24-OH-THCA) (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Defective peroxisomal cleavage of the C27-steroid side chain in the cerebro-hepato-renal syndrome of Zellweger.

Kase¹,

Björkhem²,

Hågå³

et al. 1985

J. Clin. Invest.

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Based on in vitro work with rat liver, we recently suggested that the peroxisomal fraction is most important for the oxidation of 3a,7a,12a-trihydroxy-5,8-cholestanoic acid (THCA) into cholic acid. The cerebro-hepato-renal syndrome of Zellweger is a fatal recessive autosomal disorder, the most characteristic histological feature of which is a virtual absence of peroxisomes in liver and kidneys. This disease offers a unique opportunity to evaluate the relative importance of peroxisomes in bile acid biosynthesis. A child with Zellweger syndrome was studied in the present work. In accordance with previous work, there was a considerable accumulation of THCA, 3a,7a,12a,24-tetrahydroxy-5,6-cholestanoic acid (24-OH-THCA), 3a,7a,12a-trihydroxy-27-carboxymethyl-5#6-cholestan-26-oic acid (C2-dicarboxylic acid), and 3a,7a-dihydroxy-5#-cholestanoic acid in serum. In addition, a tetrahydroxylated 51e-cholestanoic acid with all the hydroxyl groups in the steroid nucleus was found.3H-Labeled 5W-cholestane-3a,7a,12a-triol was administered intravenously together with 14C-labeled cholic acid. There was a rapid incorporation of 3H in THCA and a slow incorporation into cholic acid. The specific radioactivity of 3H in THCA was about one magnitude higher than that in cholic acid. The conversion was evaluated by following the increasing ratio between 3H and 14C in biliary cholic acid. The rate of incorporation of 3H in cholic acid was considerably less than previously reported in experiments with healthy subjects, and the maximal conversion of the triol into cholic acid was only 15-20%. About the same rate of conversion was found after oral administration of 3H-THCA. Both in the experiment with 3H-5W6cholestane-3a,7a,12a-triol and with 3H-THCA, there was an efficient incorporation of 3H in the above unidentified tetrahydroxylated 5#-cholestanoic acid. There was only slow incorporation of radioactivity into 24-OH-THCA and into the C2-dicarboxylic acid. From the specific activity decay curve of "'C in cholic acid obtained after intravenous injection of 14C-cholic acid, the pool size of cholic acid was calculated to be 24 mg/M2 and the daily production rate to 9 mg/M2 per d.This corresponds to a reduction of -85 and 90%, respectively, when compared with normal infants. It is concluded that liver peroxisomes are essential in the normal conversion of THCA to cholic acid. In the Zellweger syndrome this conversion is Address correspondence to Dr. Pedersen, Institute for Nutrition Research.Received for publication 9 January 1984 and in revised form 12 October 1984. defective, and as a consequence the accumulated THCA is either excreted as such or transformed into other metabolites by hydroxylation or side chain elongation. The accumulation of THCA, as well as the similar rate of conversion of 5#-cholestane-3a,7a,12a-triol and THCA into cholic acid, support the contention that the 26-hydroxylase pathway with intermediate formation of THCA is the most important pathway for formation of cholic acid in man.

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Defects of Bile Acid Synthesis in Zellweger's Syndrome

Cited by 173 publications

References 8 publications

Distinct signatures of host–microbial meta-metabolome and gut microbiome in two C57BL/6 strains under high-fat diet

Distinct signatures of host–microbial meta-metabolome and gut microbiome in two C57BL/6 strains under high-fat diet

Medium- and Long-Chain Dicarboxylic Aciduria in Patients with Zellweger Syndrome and Neonatal Adrenoleukodystrophy

Defective peroxisomal cleavage of the C27-steroid side chain in the cerebro-hepato-renal syndrome of Zellweger.

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