Bile acid analyses in “pseudo‐Zellweger” syndrome; clues to the defect in peroxisomal β‐oxidation

Clayton, PT; Lake, B. D.; Hjelm, Michelle; Stephenson, John B.; Besley, G. T. N.; Wanders, Ronald J. A.; Schram, A. W.; Tager, J. M.; Schutgens, R. B. H.; Lawson, A. M.

doi:10.1007/bf01804226

Cited by 41 publications

(27 citation statements)

References 8 publications

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“…Accumulation of very longchain fatty acids as well as coprostanic acidemia are found but, in the liver, peroxisomes are found to be abundant (18). The syndromes may be distinguished biochemically by a normal plasmalogen biosynthesis and no trace of C29-dicarboxylic bile acid in the Pseudo-Zellweger syndrome (19).…”

Section: Discussionmentioning

confidence: 99%

Metabolism of prostaglandin F2 alpha in Zellweger syndrome. Peroxisomal beta-oxidation is a major importance for in vivo degradation of prostaglandins in humans.

Diczfalusy¹,

Kase²,

Alexson³

et al. 1991

J. Clin. Invest.

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We have recently shown in vitro that the peroxisomal fraction of a rat liver homogenate has the highest capacity to (-oxidize prostaglandins. In order to evaluate the relative importance of peroxisomes for this conversion also in vivo, we administered [Hjprostaglandin F2. to an infant suffering from Zellweger syndrome, a congenital disorder characterized by the absence of intact peroxisomes. As a control, labeled compound was administered to two healthy volunteers. Urine was collected, fractionated on a SEP-PAK Cl3 cartridge, and subjected to reversed-phase high-performance liquid chromatography. The Zellweger patient was found to excrete prostaglandin metabolites considerably less polar than those of the control subjects. The major urinary metabolite in the control subjects was practically absent in the urine from the Zellweger patient. The major urinary prostaglandin F2. metabolite from the Zellweger patient was identified as an w-oxidized C"0-prostaglandin, 9,11-dihydroxy-15-oxoprost-5-ene-1,20-dioic acid. The major urinary prostaglandin Fu, metabolite from the control subjects had chromatographic properties of a tetranor (C16) prostaglandin, in accordance with earlier published data. The present results, in combination with our previous in vitro data, indicate that peroxisomal (i-oxidation is of major importance for in vivo chain shortening of prostaglandins. (J. Clin. Invest. 1991. 88:978-984.)

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Section: Discussionmentioning

confidence: 99%

Metabolism of prostaglandin F2 alpha in Zellweger syndrome. Peroxisomal beta-oxidation is a major importance for in vivo degradation of prostaglandins in humans.

Diczfalusy¹,

Kase²,

Alexson³

et al. 1991

J. Clin. Invest.

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“…By contrast, enzyme hydrolysis of bile from I.B. and N.B., the two siblings with suspected thiolase or 3-hydroxyacyl-CoA dehydrogenase deficiency (10) yielded a similar mixture of bile acids to that found in the bile from L.C. (TableII).…”

Section: Introductionmentioning

confidence: 85%

Bile acid profiles in peroxisomal 3-oxoacyl-coenzyme A thiolase deficiency.

Clayton¹,

Patel²,

Lawson³

et al. 1990

J. Clin. Invest.

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Fast atom bombardment mass spectrometry and gas chromatography-mass spectrometry were used to analyze bile acids in the body fluids of an infant (L.C.) whose liver contained no immunoreactive peroxisomal 3-oxoacyl-CoA thiolase. The profiles were compared with those of six patients with undetectable peroxisomes (Zellweger syndrome) and two siblings (N.B. and I.B.) whose defect of peroxisomal fl-oxidation could not be localized by morphological studies of peroxisomes or by immunoblotting of peroxisomal fl-oxidation proteins.

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“…Patients with a deficiency of DBP accumulate C27-bile acid intermediates, but there are still mature C24-bile acids present in their plasma and bile (4,5). This suggests that an alternative pathway for bile acid biosynthesis exists, which does not involve DBP.…”

mentioning

confidence: 89%

Developmental Changes of Bile Acid Composition and Conjugation in L- and D-Bifunctional Protein Single and Double Knockout Mice

Ferdinandusse

Denis

Overmars

et al. 2005

Journal of Biological Chemistry

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Peroxisomal ␤-oxidation is an essential step in bile acid synthesis, since it is required for shortening of C27-bile acid intermediates to produce mature C24-bile acids. D-Bifunctional protein (DBP) is responsible for the second and third step of this ␤-oxidation process. However, both patients and mice with a DBP deficiency still produce C24-bile acids, although C27-intermediates accumulate. An alternative pathway for bile acid biosynthesis involving the peroxisomal L-bifunctional protein (LBP) has been proposed. We investigated the role of LBP and DBP in bile acid synthesis by analyzing bile acids in bile, liver, and plasma from LBP, DBP, and LBP:DBP double knock-out mice. Bile acid biosynthesis, estimated by the ratio of C27/C24-bile acids, was more severely affected in double knock-out mice as compared with DBP؊/؊ mice but was normal in LBP؊/؊ mice. Unexpectedly, trihydroxycholestanoyl-CoA oxidase was inactive in double knock-out mice due to a peroxisomal import defect, preventing us from drawing any firm conclusion about the potential role of LBP in an alternative bile acid biosynthesis pathway. Interestingly, the immature C27-bile acids in DBP and double knock-out mice remained unconjugated in juvenile mice, whereas they occurred as taurine conjugates after weaning, probably contributing to the minimal weight gain of the mice during the lactation period. This correlated with a marked induction of bile acyl-CoA:amino acid N-acyltransferase expression and enzyme activity between postnatal days 10 and 21, whereas the bile acyl-CoA synthetases increased gradually with age. The nuclear receptors hepatocyte nuclear factor-4␣, farnesoid X receptor, and peroxisome proliferator receptor ␣ did not appear to be involved in the up-regulation of the transferase.

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Bile acid analyses in “pseudo‐Zellweger” syndrome; clues to the defect in peroxisomal β‐oxidation

Cited by 41 publications

References 8 publications

Metabolism of prostaglandin F2 alpha in Zellweger syndrome. Peroxisomal beta-oxidation is a major importance for in vivo degradation of prostaglandins in humans.

Metabolism of prostaglandin F2 alpha in Zellweger syndrome. Peroxisomal beta-oxidation is a major importance for in vivo degradation of prostaglandins in humans.

Bile acid profiles in peroxisomal 3-oxoacyl-coenzyme A thiolase deficiency.

Developmental Changes of Bile Acid Composition and Conjugation in L- and D-Bifunctional Protein Single and Double Knockout Mice

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