Developmental pattern of 3-oxo-Delta 4 bile acids in neonatal bile acid metabolism

Inoue, Toshiro; Kimura, Akihiko; Aoki, Kumiko; Tohma, Masahiko; Kato, Hirohisa

doi:10.1136/fn.77.1.f52

Cited by 24 publications

(34 citation statements)

References 17 publications

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“…In the fetus and in newborns prior to infancy, 3-oxo-⌬ 4 bile acid intermediate levels are high and similar to the levels observed in the patients (31). However, within the first months of early childhood, these levels dropped significantly, indicating up-regulation of bile acid synthesis and onset of 5␤-reductase activity.…”

Section: Discussionsupporting

confidence: 73%

Characterization of Disease-related 5β-Reductase (AKR1D1) Mutations Reveals Their Potential to Cause Bile Acid Deficiency

Drury

Mindnich

Penning

2010

Journal of Biological Chemistry

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Bile acid deficiency is a serious syndrome in newborns that can result in death if untreated. 5␤-Reductase deficiency is one form of bile acid deficiency and is characterized by dramatically decreased levels of physiologically active 5␤-reduced bile acids. AKR1D1 (aldo-keto reductase 1D1) is the only known human enzyme that stereo-specifically reduces the ⌬ 4 double bond in 3-keto steroids and sterols to yield the 5␤-hydrogenated product. Analysis of the AKR1D1 gene in five patients with 5␤-reductase deficiency revealed five different mutations resulting in an amino acid substitution in the protein. To investigate a causal role for these observed point mutations in AKR1D1 in 5␤-reductase deficiency, we characterized their effect on enzymatic properties. Attempts to purify mutant enzymes by overexpression in Escherichia coli only yielded sufficient amounts of the P133R mutant for further characterization. This enzyme displayed a highly reduced K m and V max reminiscent of uncompetitive kinetics with 4-cholesten-7␣-ol-3-one as substrate. In addition, this mutant displayed no change in cofactor affinity but was more thermolabile in the absence of NADPH as judged by CD spectroscopy. All mutants were compared following expression in HEK 293 cells. Although these enzymes were equally expressed based on mRNA levels, protein expression and functional activity were dramatically reduced. Cycloheximide treatment also revealed that several of the expressed mutants were less stable. Our findings show that the reported mutations in AKR1D1 in patients with 5␤-reductase lead to significantly decreased levels of active enzyme and could be causal in the development of bile acid deficiency syndrome.AKR1D1 (aldo-keto reductase 1D1) is implicated as one of the key enzymes in bile acid biosynthesis. The enzyme is the only known human ⌬ 4 -3-ketosteroid 5␤-reductase and catalyzes the reduction of the ⌬ 4 -3-ketosteroid to form the A/B cis ring structure, utilizing NADPH as a cofactor (1). The ⌬ 4 -3-ketosteroid functionality is common to all steroid hormones except the estrogens, and the C4-C5 double bond can be further reduced in a stereo-specific manner. 5␣-Reduction of testosterone to 5␣-dihydrotestosterone results in increased androgen receptor activation (2, 3), whereas 5␤-reduction of progesterone to 5␤-pregnane-3,20-dione results in activation of the pregnane X receptor (4) and constitutive active/androstane receptor (5). In bile acid biosynthesis, AKR1D1 reduces ⌬ 4 -cholesten-

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Section: Discussionsupporting

confidence: 73%

Characterization of Disease-related 5β-Reductase (AKR1D1) Mutations Reveals Their Potential to Cause Bile Acid Deficiency

Drury

Mindnich

Penning

2010

Journal of Biological Chemistry

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“…Similar information has been reported by Boehn et al [15]. However, this finding in preterm infants differed from that in full-term infants [1,2,4]. The urinary concentration of total bile acids in the full-term infants increased between birth and 7 days, and gradually decreased thereafter [1,4].…”

Section: Discussionsupporting

confidence: 72%

“…Since 1994, we have studied the developmental pattern of the usual and unusual bile acids, such as unsaturated ketonic bile acids and 1ß-and 7ß-hydroxylated bile acids, in the urine of full-term healthy infants [1][2][3][4]. Several other research groups have reported finding unusual bile acids in the amniotic fluid [5,6], meconium [7,8], umbilical cord blood [5,9] and in the bile from the fetal gallbladder [10,11].…”

Section: Introductionmentioning

confidence: 99%

Fetal Bile Acid Metabolism: Analysis of Urinary 3β-Monohydroxy-Δ<sup>5</sup> Bile Acid in Preterm Infants

Yamato

Kimura²,

Inoue³

et al. 2001

Neonatology

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To elucidate the urinary concentration of total bile acids after birth and the profile of the usual and unusual urinary bile acids, especially 3β-hydroxy-5-cholen-24-oic acid (Δ⁵-3β-ol), we measured the concentrations of 13 bile acids in the urine from preterm infants vs. full-term controls by gas chromatography-mass spectrometry. The urinary concentration of total bile acids in early preterm infants below 32 weeks of gestational age significantly exceeded that of the late preterm and full-term infants (p < 0.0005). The major urinary bile acids in early preterm infants were cholic acid, 1β,3α,7α,12α-tetrahydroxy-5β-cholan-24-oic acid and Δ⁵-3β-ol. In conclusion, the high urinary concentrations of total bile acids in preterm infants may be due to an overproduction, or more likely to a low hepatic bile acid clearance. An alternative fetal pathway, the acidic pathway, may be a major route of bile acid biosynthesis in preterm infants.

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“…This protein has no known function but contains zinc finger domains that may imply a transcription factor activity. 3-Oxo-5-␤-steroid 4-dehydrogenase is necessary in bile acid synthesis (31) and as such may have a role in the hypercholesterolemia that accompanies diabetes. D-Dopachrome tautomerase was downregulated in diabetes and is an inflammatory mediator important in T cell and macrophage migration inhibition (47,63) with no established role in diabetes beyond that ketones are effective inhibitors of this enzyme (19).…”

Section: Ajp-endocrinol Metabmentioning

confidence: 99%

Proteomic changes associated with diabetes in the BB-DP rat

Johnson

Harris²,

French

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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These studies were structured with the aim of utilizing emerging technologies in two-dimensional (2D) gel electrophoresis and mass spectrometry to evaluate protein expression changes associated with type 1 diabetes. We reasoned that a broad examination of diabetic tissues at the protein level might open up novel avenues of investigation of the metabolic and signaling pathways that are adversely affected in type 1 diabetes. This study compared the protein expression of the liver, heart, and skeletal muscle of diabetes-prone rats and matched control rats by semiquantitative liquid chromatography-mass spectrometry and differential in-gel 2D gel electrophoresis. Differential expression of 341 proteins in liver, 43 in heart, and 9 (2D gel only) in skeletal muscle was detected. These data were assembled into the relevant metabolic pathways affected primarily in liver. Multiple covalent modifications were also apparent in 2D gel analysis. Several new hypotheses were generated by these data, including mechanisms of net cytosolic protein oxidation, formaldehyde generation by the methionine cycle, and inhibition of carbon substrate oxidation via reduction in citrate synthase and short-chain acyl-CoA dehydrogenase. metabolism; acyl carnitine; citrate synthase; methionine; liver; heart; skeletal muscle; mass spectroscopy; two-dimensional gel electrophoresis ALTHOUGH EXTENSIVELY STUDIED, type 1 diabetes remains a major health concern, and much of the pathogenesis still eludes understanding. In the Diabetes Control and Complications Trial, the most strongly regulated subjects still developed complications despite aggressive intervention (35). The fundamental pathology of type 1 diabetes is the loss of pancreatic ␤-cell function and the related release of insulin in the regulation of overall metabolic functions of the body. The complications of type 1 diabetes include dramatically altered energy metabolism and glucose handling, protein oxidation, vascular disease, heart disease, retinopathy, neuropathies, nephropathy, and susceptibility to infections. These results showed that the pathology of diabetes exceeds the simple maintenance of plasma glucose and insulin levels. A more global assessment of the diabetic state may provide useful insight. These studies sought to perform a comprehensive screen of the proteomic changes associated with the type 1 diabetic state, utilizing emerging technology in high-throughput semiquantitative proteomics and two-dimensional (2D) gel electrophoresis to detect protein expression differences as well as possible covalent modifications inherent to the diabetic state.Previous studies have revealed that many enzymes and proteins are under transitional control by insulin (45) that would predictably alter the content of these proteins with the reduction of insulin in type 1 diabetes. The major transcription factors involved in insulin action are adipocyte differentiation and determination factor (ADD)-1/sterol regulatory element binding protein (SREBP)-1/peroxisome proliferator-activated receptor (PP...

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Developmental pattern of 3-oxo-Delta 4 bile acids in neonatal bile acid metabolism

Cited by 24 publications

References 17 publications

Characterization of Disease-related 5β-Reductase (AKR1D1) Mutations Reveals Their Potential to Cause Bile Acid Deficiency

Characterization of Disease-related 5β-Reductase (AKR1D1) Mutations Reveals Their Potential to Cause Bile Acid Deficiency

Fetal Bile Acid Metabolism: Analysis of Urinary 3β-Monohydroxy-Δ<sup>5</sup> Bile Acid in Preterm Infants

Proteomic changes associated with diabetes in the BB-DP rat

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