The bile acid synthetic gene 3β-hydroxy-Δ5-C27-steroid oxidoreductase is mutated in progressive intrahepatic cholestasis

Schwarz, Margrit; Wright, Angelique C.; Davis, Dana; Nazer, Hisham M.; Björkhem, Ingemar; Russell, David W.

doi:10.1172/jci10902

Cited by 99 publications

(76 citation statements)

References 32 publications

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“…1A). Concordant with the results of the microarray analysis, mRNA levels for 3␤-hydroxy-⌬ 5 -C 27 -steroid oxidoreductase (3␤-HSD) (33) and GABA(A) receptor-associated protein-like 1 (Gabarapl1) (34) were higher at ZT6 than ZT18 and those for Spot14, Hspa8, Hspa5, and Hsp84-1 were higher at ZT18 than ZT6. We also performed Northern analysis by using poly(A) ϩ RNA-derived sense strand cRNA (Fig.…”

Section: Resultssupporting

confidence: 73%

Two-peaked Synchronization in Day/Night Expression Rhythms of the Fibrinogen Gene Cluster in the Mouse Liver

Sakao

Ishihara

Horikawa

et al. 2003

Journal of Biological Chemistry

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Genes expressed with day/night rhythms in the mouse liver were searched for by microarray analysis using an in-house array harboring mouse liver cDNAs. The rhythmic expression with a single peak and trough level was confirmed by RNA blot analysis for 3␤-Hsd and Gabarapl1 genes exhibiting a peak in the light phase and Spot14, Hspa8, Hspa5, and Hsp84-1 genes showing a peak in the dark phase. On the other hand, mRNA levels for all of the three fibrinogen subunits, A␣, B␤ and ␥, exhibited two peaks each in the light and dark phases in a synchronized manner. This two-peaked rhythmic pattern of fibrinogen genes as well as the single peaktrough pattern of other genes was diminished or almost completely lost in the liver of Clock mutant mice, suggesting that the two-peaked expression is also under the control of oscillation-generating genes. In constant darkness, the first peak of the expression rhythm of fibrinogen genes was almost intact, but the second peak disappeared. Therefore, although the first peak in the subjective day is a component of the innate circadian rhythm, the second peak seems to require light stimuli. Fasting in constant darkness caused shifts of time phases of the circadian rhythms. Protein levels of the fibrinogen subunits in whole blood also exhibited circadian rhythms. In the mouse and human loci of the fibrinogen gene cluster, a number of sequence elements resembling circadian transcription factor-binding sites were found. The fibrinogen gene locus provides a unique system for the study of two-peaked day/night rhythms of gene expression in a synchronized form.In mammals, intracellular oscillation generators for circadian rhythms reside in various peripheral organs such as liver as well as in the central pacemaker, the suprachiasmatic nucleus (SCN) 1 of the hypothalamus (1, 2). The SCN and peripheral tissues seem to share common molecular mechanisms for generating the circadian oscillation. The widely accepted mechanism is autoregulatory feedback inhibition of period (Per) and cryptochrome (Cry) genes by their own protein products in antagonism with the positive transcription factor of the CLOCK-BMAL1 heterodimer (3-8).The time phase of the SCN oscillator is adjusted by light stimuli everyday in the light-dark condition (1, 2). The SCN then controls or affects the oscillators of peripheral cells in both relatively direct and indirect manners. The liver provides a well characterized example of these regulations. Although oscillation generators of liver cells are under the circadian control of glucocorticoids (9, 10), presumably through the hypothalamus-hypophysis-adrenal axis, time phases of the liver oscillators are more profoundly affected by feeding time (11-13). Artificial diurnal feeding of nocturnal rodents can completely uncouple the oscillation phase of the liver from that of the SCN. Seemingly, the SCN regulates the liver oscillators indirectly by controlling the sleep-awakeness phase that in turn determines the feeding time under the natural condition.Recently, hundreds of genes exhibit...

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Section: Resultssupporting

confidence: 73%

Two-peaked Synchronization in Day/Night Expression Rhythms of the Fibrinogen Gene Cluster in the Mouse Liver

Sakao

Ishihara

Horikawa

et al. 2003

Journal of Biological Chemistry

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“…CYP27A1, and 3␤-hydroxy-⌬ 5 -C 27 -steroid oxidoreductase (3␤HSD), from David Russell, University of Texas Southwestern Medical Center (13,14). Probes for other mouse genes were generated by RT-PCR using the following primers (GenBank accession numbers are provided in parentheses): constitutive androstane receptor (CAR) (AF009327) 5Ј-GGAATTCGGA-ATG and 5Ј-GCGGATGGCCTCAA; cytochrome P450 2B10 (CYP2B10) (NM 009998.1) 5Ј-GGCTTCTTGCTACTCT-TAGC and 5Ј-ATTTCCACCAGCTGTCTCAG; cytochrome P450 3A11 (CYP3A11) (NM 007818.1) 5Ј-TTTTCTGTCT-TCACAAACCGG and 5Ј-CAAACCTCATGCCAATGCAG; sterol 12␣-hydroxylase (CYP8B1) (AF090317) 5Ј-GGGTAC-CAGTCTGTAGATGG and 5Ј-AGTCTCTGGTGGAAGA-GACG; multidrug resistance-associated protein 2 (MRP2) (AF227274) 5Ј-GACTCTGACAACTTGAATGGGACC and 5Ј-CCTTCTCTCCGCTCTTGATGTTAC; organic anion transporter polypeptide (OATP2) (NM 030687) 5Ј-CATGTG-CATATGTATCCAAATCAC and 5Ј-CCTCATCACAGCT-TAGTTTTCCGT; and small heterodimer partner (SHP) (L76567) 5Ј-AAGGATCCGCTGGGAAGAAACAGGAA-CAAG and 5Ј-CTAGCTAGCTGGAGGCACCAGACTC-CATTC.…”

Section: Methodsmentioning

confidence: 99%

Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor

Goodwin

Gauthier

Umetani

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

179

128

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Sterol 27-hydroxylase (CYP27A1) is required for bile acid synthesis by both the classical and alternate pathways. Cyp27a1 ؊/؊ mice exhibit a dramatic increase in the activity of cytochrome P450 3A (CYP3A), which catalyzes side-chain hydroxylations of bile acid intermediates, thereby facilitating their excretion in the bile and urine. We examine the role of the nuclear xenobiotic receptor PXR (pregnane X receptor) in this process. We demonstrate that expression of Cyp3a11 and other established PXR target genes is increased in the Cyp27a1 ؊/؊ mice. WhenCyp27a1 ؊/؊ mice are fed a diet containing either cholic acid or chenodeoxycholic acid, expression of CYP7A1, which catalyzes the rate-limiting step in bile acid biosynthesis, is strongly suppressed. In parallel, the induction of Cyp3a11 observed in these mice is reversed, suggesting that bile acid intermediates serve as PXR activators. In support of this hypothesis, three potentially toxic sterols (7␣-hydroxy-4-cholesten-3-one, 5␤-cholestan-3␣,7␣,12␣-triol, and 4-cholesten-3-one), including two that are known to accumulate in Cyp27a1 ؊/؊ mice, are efficacious activators of mouse PXR. All three compounds are more potent activators of mouse PXR than of human PXR, which may explain in part why humans who lack functional CYP27A1 do not display a corresponding increase in CYP3A activity and are stricken with the disease cerebrotendinous xanthomatosis. Taken together, these results reveal the existence of a feedforward regulatory loop by which potentially toxic bile acid intermediates activate PXR and induce their own metabolism. In addition, this study demonstrates that animal models with alterations in gene expression can be used to identify endogenous ligands for orphan nuclear receptors.

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“…In the first reported patient, complete absence of 3␤-HSD activity was found by Buchmann et al in 1990 (2) based on the study of cultured fibroblasts. In 2000, Schwarz et al (3) reported that the same patient had a homozygous mutation representing a 2-bp deletion in exon 6 of the 3␤-HSD gene (HSD3B7) on chromosome 16p11.2-12. The human HSD3B7 gene contains six coding exons and encodes 369 amino acids; so far, 13 distinct mutations causing 3␤-HSD deficiency have been reported (4,5).…”

Section: Eficiency Of 3␤-hydroxy-⌬mentioning

confidence: 99%

Molecular Genetic and Bile Acid Profiles in Two Japanese Patients With 3β-Hydroxy-Δ5-C27-Steroid Dehydrogenase/Isomerase Deficiency

et al. 2010

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ABSTRACT:We report definitive diagnosis and effective chenodeoxycholic acid (CDCA) treatment of two Japanese children with 3␤-hydroxy-⌬ 5 -C 27 -steroid dehydrogenase/isomerase deficiency. Findings of cholestasis with normal serum ␥-glutamyltransferase activity and total bile acid concentration indicated the need for definitive bile acid analysis. Large amounts of 3␤-hydroxy-⌬ 5 bile acids were detected by gas chromatography-mass spectrometry. HSD3B7 gene analysis using peripheral lymphocyte genomic DNA from the patients and their parents identified four novel mutations of the HSD3B7 gene in the patients. One had a homozygous mutation, 314delA; the other had compound heterozygous mutations: V132F, T149I, and 973_974insCCTGC. Interestingly, the second patient's mother had V132F and T149I mutations in one allele. Excessive 3␤-hydroxy-⌬ 5 -bile acids such as 3␤,7␣-dihydroxy-and 3␤,7␣,12␣-trihydroxy-5-cholenoic acids were detected in the first patient's urine; the second patient's urine contained large amounts of 3␤-hydroxy-5-cholenoic acid. Liver dysfunction in both patients decreased with ursodeoxycholic acid treatment, but unusual bile acids were still detected. Normalization of the patients' liver function and improvement of bile acid profiles occurred with CDCA treatment. Thus, we found mutations in the HSD3B7 gene accounting for autosomal recessive neonatal cholestasis caused by 3␤-hydroxy-⌬ 5 -C 27 -steroid dehydrogenase/isomerase deficiency. Early neonatal diagnosis permits initiation of CDCA treatment at this critical time, before the late cholestatic stage. (Pediatr Res 68: 258-263, 2010) D eficiency of 3␤-hydroxy-⌬ 5 -C 27 -steroid dehydrogenase/ isomerase (3␤-HSD) was first described by Clayton et al. in 1987 (1). This inborn error of bile acid synthesis is very rare and shows autosomal recessive inheritance. The main findings in 3␤-HSD deficiency are low or normal concentrations of total bile acid and normal activity of ␥-glutamyltransferase (GGT) in serum, as well as absence of pruritus despite conjugated hyperbilirubinemia, elevated alanine aminotransferase (ALT), and fatty stools. In the synthesis of bile acids from cholesterol, 3␤-HSD catalyzes the second of a series of reactions leading to excretion of 3␤,7␣-dihydroxy-5-cholenoic acid (⌬ 5 -3␤,7␣-diol) and 3␤,7␣,12␣-trihydroxy-5-cholenoic acid (⌬ 5 -3␤,7␣,12␣-triol) in the urine. In the first reported patient, complete absence of 3␤-HSD activity was found by Buchmann et al. in 1990 (2) based on the study of cultured fibroblasts. In 2000, Schwarz et al. (3) reported that the same patient had a homozygous mutation representing a 2-bp deletion in exon 6 of the 3␤-HSD gene (HSD3B7) on chromosome 16p11.2-12. The human HSD3B7 gene contains six coding exons and encodes 369 amino acids; so far, 13 distinct mutations causing 3␤-HSD deficiency have been reported (4,5).Here, we report genetic analyses of two Japanese patients with 3␤-HSD deficiency: one previously reported patient (6,7) was diagnosed with 3␤-HSD deficiency by bile acid analysis and the ot...

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The bile acid synthetic gene 3β-hydroxy-Δ5-C27-steroid oxidoreductase is mutated in progressive intrahepatic cholestasis

Cited by 99 publications

References 32 publications

Two-peaked Synchronization in Day/Night Expression Rhythms of the Fibrinogen Gene Cluster in the Mouse Liver

Two-peaked Synchronization in Day/Night Expression Rhythms of the Fibrinogen Gene Cluster in the Mouse Liver

Identification of bile acid precursors as endogenous ligands for the nuclear xenobiotic pregnane X receptor

Molecular Genetic and Bile Acid Profiles in Two Japanese Patients With 3β-Hydroxy-Δ5-C27-Steroid Dehydrogenase/Isomerase Deficiency

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