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Bile acid profiles in a peroxisomal D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional
1Institute of Pharmaceutical Sciences, Hiroshima University School of Medicine.
Insights
Infants with D-bifunctional protein deficiency accumulate C27 bile acid intermediates, similar to other peroxisomal disorders. This accumulation is linked to impaired side-chain cleavage in bile acid biosynthesis due to the D-bifunctional protein defect.
Area of Science:
- Biochemistry
- Genetics
- Metabolic Disorders
Background:
- Peroxisomal disorders, such as Zellweger syndrome, involve complex metabolic disruptions.
- Bile acid biosynthesis is a critical pathway affected in various genetic conditions.
Purpose of the Study:
- To analyze bile acid profiles in an infant with D-bifunctional protein deficiency.
- To identify the specific bile acid intermediates accumulating in this condition.
- To elucidate the role of D-bifunctional protein in bile acid biosynthesis.
Main Methods:
- Gas-liquid chromatography (GLC)
- Gas-liquid chromatography-mass spectrometry (GLC-MS)
- High-performance liquid chromatography (HPLC)
Main Results:
- Significant accumulation of C27 bile acid intermediates was observed in serum (74%), urine (59%), and bile (35%).
- Major C27 bile acids identified were (24R,25R)- and (24R,25S)-3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestanoic acids.
- Presence of other peroxisomal enzymes (acyl-CoA oxidase, L-bifunctional protein, thiolase) suggests a specific defect in D-bifunctional protein.
Conclusions:
- D-bifunctional protein deficiency leads to the accumulation of C27 bile acid intermediates.
- The defect in D-bifunctional protein impairs the oxidative side-chain cleavage in bile acid biosynthesis.
- Findings highlight the critical role of D-bifunctional protein in normal bile acid metabolism.
Abstract:
Bile acid profiles in serum, urine and bile from an infant with a peroxisomal D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein (D-bifunctional protein) deficiency were analyzed by means of gas-liquid chromatography, gas-liquid chromatography-mass spectrometry, and high-performance liquid chromatography. As in such several peroxisomal disorders as Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease, the accumulation of C27-bile acid intermediates was also demonstrated in the infant with D-bifunctional protein deficiency, accounting for 74% of the total bile acids in serum, 59% in urine, and 35% in bile. In addition, the major constituents of the C27-bile acids were (24R,25R)- and (24R,25S)-3alpha,7alpha,12alpha,24-tetrahydroxy-5be ta-cholestanoic acids along with small amounts of their 24S counterparts. Since immunoreactive acyl-CoA oxidase, L-bifunctional protein, and thiolase were all present in the liver, the impairment of the oxidative side-chain cleavage in bile acid biosynthesis is considered to be due to the defect of D-bifunctional protein.