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1.
Zhonghua Er Ke Za Zhi ; 62(9): 877-882, 2024 Sep 02.
Artículo en Chino | MEDLINE | ID: mdl-39192447

RESUMEN

Objective: To summarize the clinical features and genetic characteristics of Congenital bile acid synthetic disorder type 3 (BASD3) disorder caused by CYP7B1 gene variation. Methods: This was a case series study. Clinical data and genetic results of 2 cases of congenital bile acid synthetic disorder type 3 caused by CYP7B1 gene variations in the Department of Infectious Diseases, Children's Hospital of Fudan University at Xiamen and Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University from January 2021 to December 2023 were retrospectively collected and analyzed. Literature up to December 2023 was searched from electronic databases of China National Knowledge Infrastructure (CNKI), Wanfang Data and PubMed with the combined keywords of " Congenital bile acid synthetic disorder type 3""Oxysterol 7-alpha-hydroxylase""Oxysterol 7α-Hydroxylase Deficiency""BASD3" and "CYP7B1 liver" both in Chinese and English. The main clinical features and genetic characteristics of BASD3 disorder caused by CYP7B1 gene variations were summarized. Results: Two BASD3 patients, 1 male and 1 female, were admitted at the ages of 3 months and 18 days, and 2 months and 7 days, respectively. Both patients presented with neonatal cholestasis and hepatomegaly. Biochemical evidence indicated direct hyper-bilirubinemia with elevated aminotransferase levels, while gamma-glutamyltransferase (GGT) and total bile acid levels were normal or nearly normal. Patient 1 was a compound heterozygotes of the CYP7B1 gene variants c.525-526insCAAGTTGG(p.Asp176GInfs*15) and c.334C>T(p.Arg112Ter). Patient 1 jaundice resolved and liver function tests normalized after oral administration of chenodeoxycholic acid (CDCA). Patient 2 was homozygous for variant c.334C>T(p.Arg112Ter) in CYP7B1 gene. Patient 2 was in liver failure status already and not reactive to oral CDCA administration. Patient 2 received living-related liver transplantation for enhanced abdominal CT revealed a liver tumor likely vascular origin. Literature review revealed no cases of BASD3 reported in Chinese literature, including 2 patients in this study, while 12 patients (9 males and 3 females) were reported in 9 English literatures. All of the 12 manifested jaundice and hepatosplenomegaly in infancy, with cirrhosis, liver failure, kidney enlargement, hypoglycemia, and spontaneous bleeding in some cases, polycystic kidney disease was demonstrated in 5 cases of them. The c.334C>T (p.Arg112Ter) of the CYP7B1 gene was homozygous in 4 cases and compound heterozygous in 2 cases. Among the 12 children, 6 cases received CDCA treatment, while 6 cases not. Four survived with their native liver in the 6 cases who received CDCA therapy, while none in the 6 cases not received CDCA therapy. Conclusions: BASD3 is a rare hereditary cholestatic disorder. Markedly elevated levels of conjugated bilirubin and aminotransferases, with normal or nearly normal GGT and total bile acid levels can serve as diagnostic clue. c.334C>T is the most common pathogenic variant of the CYP7B1 gene. Timely administration of CDCA may save the liver.


Asunto(s)
Colestasis , Familia 7 del Citocromo P450 , Mutación , Errores Congénitos del Metabolismo Esteroideo , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Ácidos y Sales Biliares/metabolismo , Ácidos y Sales Biliares/sangre , Familia 7 del Citocromo P450/genética , Hígado/metabolismo , Estudios Retrospectivos , Esteroide Hidroxilasas , Colestasis/diagnóstico , Colestasis/tratamiento farmacológico , Colestasis/genética , Errores Congénitos del Metabolismo Esteroideo/diagnóstico , Errores Congénitos del Metabolismo Esteroideo/tratamiento farmacológico , Errores Congénitos del Metabolismo Esteroideo/genética
2.
Int J Mol Sci ; 25(9)2024 Apr 27.
Artículo en Inglés | MEDLINE | ID: mdl-38731981

RESUMEN

We aimed to analyze the association between CYP7B1 and prostate cancer, along with its association with proteins involved in cancer and metabolic processes. A retrospective analysis was performed on 390 patients with prostate cancer (PC) or benign prostatic hyperplasia (BPH). We investigated the interactions between CYP7B1 expression and proteins associated with PC and metabolic processes, followed by an analysis of the risk of biochemical recurrence based on CYP7B1 expression. Of the 139 patients with elevated CYP7B1 expression, 92.8% had prostate cancer. Overall, no increased risk of biochemical recurrence was associated with CYP7B1 expression. However, in a non-diabetic subgroup analysis, higher CYP7B1 expression indicated a higher risk of biochemical recurrence, with an HR of 1.78 (CI: 1.0-3.2, p = 0.05). PC is associated with elevated CYP7B1 expression. In a subgroup analysis of non-diabetic patients, elevated CYP7B1 expression was associated with an increased risk of biochemical recurrence, suggesting increased cancer aggressiveness.


Asunto(s)
Biomarcadores de Tumor , Familia 7 del Citocromo P450 , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/genética , Biomarcadores de Tumor/metabolismo , Anciano , Familia 7 del Citocromo P450/metabolismo , Familia 7 del Citocromo P450/genética , Persona de Mediana Edad , Progresión de la Enfermedad , Estudios Retrospectivos , Hiperplasia Prostática/metabolismo , Hiperplasia Prostática/patología , Inmunohistoquímica , Análisis de Matrices Tisulares , Recurrencia Local de Neoplasia/metabolismo , Esteroide Hidroxilasas
4.
Int J Mol Sci ; 23(5)2022 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-35269552

RESUMEN

(1) Background: Synovial fluid (SF) from knee joints with osteoarthritis (OA) has increased levels of phospholipids (PL). We have reported earlier that TGF-ß and IGF-1 stimulate fibroblast-like synoviocytes (FLS) to synthesize increased amounts of PLs. The current study examined whether IL-1ß induces the release of PLs in FLS and the underlying mechanism. (2) Methods: Cultured human OA FLS were treated with IL-1ß alone and with pathway inhibitors or with synthetic liver X receptor (LXR) agonists. Cholesterol hydroxylases, ABC transporters, apolipoproteins (APO), LXR, sterol regulatory binding proteins (SREBPs), and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) were analyzed by RT-PCR, Western blot, and ELISA. The release of radiolabeled PLs from FLS was determined, and statistical analysis was performed using R (N = 5-9). (3) Results: Like synthetic LXR agonists, IL-1ß induced a 1.4-fold greater release of PLs from FLS. Simultaneously, IL-1ß upregulated the level of the PL transporter ABCA1 and of cholesterol hydroxylases CH25H and CYP7B1. IL-1ß and T0901317 stimulated the expression of SREBP1c, whereas only T0901317 enhanced SREBP2, HMGCR, APOE, LXRα, and ABCG1 additionally. (4) Conclusions: IL-1ß partially controls PL levels in OA-SF by affecting the release of PLs from FLS. Our data show that IL-1ß upregulates cholesterol hydroxylases and thus the formation of oxysterols, which, as natural agonists of LXR, increase the level of active ABCA1, in turn enhancing the release of PLs.


Asunto(s)
Benzoatos/farmacología , Bencilaminas/farmacología , Interleucina-1beta/farmacología , Osteoartritis/metabolismo , Fosfolípidos/metabolismo , Sinoviocitos/citología , Transportador 1 de Casete de Unión a ATP/genética , Células Cultivadas , Familia 7 del Citocromo P450/genética , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Receptores X del Hígado/genética , Osteoartritis/genética , Esteroide Hidroxilasas/genética , Líquido Sinovial/citología , Líquido Sinovial/efectos de los fármacos , Líquido Sinovial/metabolismo , Sinoviocitos/efectos de los fármacos , Sinoviocitos/metabolismo
5.
Exp Cell Res ; 410(1): 112952, 2022 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-34848206

RESUMEN

Septic arthritis induced by Staphylococcus aureus (S. aureus) causes irreversible cartilage degradation and subsequent permanent joint dysfunction. Recently, cartilage degradation in osteoarthritis is recognized to be associated with metabolic disorders. However, whether cholesterol metabolism is linked to septic arthritis pathology remains largely unknown. Here, we found that exposure to fermentation supernatant (FS) of S. aureus in chondrocytes resulted in a significant increase in expression of key modulators involved in cholesterol metabolism, including lectin-type oxidized low density lipoprotein receptor 1 (LOX1), cholesterol 25-hydroxylase (CH25H), 25- hydroxycholesterol 7α-hydroxylase (CYP7B1) as well as retinoic acid-related orphan receptor alpha (RORα), a binding receptor for cholesterol metabolites. We further demonstrated that enhancement of CH25H/CYP7B1/RORα axis resulted from FS exposure was mediated by activation of NF-κB signaling, along with upregulation in catabolic factors including matrix metallopeptidases (MMP3 and MMP13), aggrecanase-2 (ADAMTS5), and nitric oxide synthase-2 (NOS2) in chondrocytes. Exogenous cholesterol acts synergistically with FS in activating NF-κB pathway and increases cholesterol metabolism. While, the addition of tauroursodeoxycholic acid (TUDCA) which promotes cholesterol efflux, resulted in remarkable reduction of intracellular cholesterol level and restoration of balance between anabolism and catabolism in FS treated chondrocytes. Collectively, our data indicated that, in response to FS of S. aureus, NF-κB signaling activation coupled with increased cholesterol metabolism to stimulate catabolic factors in chondrocytes, highlighting cholesterol metabolism as a potential therapeutic target for treating septic arthritis.


Asunto(s)
Artritis Infecciosa/genética , Cartílago/crecimiento & desarrollo , Osteoartritis/genética , Staphylococcus aureus/patogenicidad , Proteína ADAMTS5/genética , Artritis Infecciosa/microbiología , Artritis Infecciosa/patología , Cartílago/metabolismo , Cartílago/microbiología , Cartílago/patología , Células Cultivadas , Colesterol/genética , Condrocitos/metabolismo , Condrocitos/microbiología , Condrocitos/patología , Familia 7 del Citocromo P450/genética , Regulación de la Expresión Génica/genética , Humanos , Metaloproteinasa 13 de la Matriz/genética , Metabolismo/genética , FN-kappa B/genética , Óxido Nítrico Sintasa de Tipo II/genética , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Osteoartritis/microbiología , Osteoartritis/patología , Receptores Depuradores de Clase E/genética , Transducción de Señal/genética , Esteroide Hidroxilasas/genética , Ácido Tauroquenodesoxicólico/genética , Factor de Transcripción ReIA/genética
6.
Genes (Basel) ; 12(12)2021 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-34946825

RESUMEN

Biallelic mutations in the CYP7B1 gene lead to spastic paraplegia-5 (SPG5). We report herein the case of a patient whose clinical symptoms began with progressive lower limb spasticity during childhood, and who secondly developed amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) at the age of 67 years. Hereditary spastic paraplegia (HSP) gene analysis identified the compound heterozygous mutations c.825T>A (pTyr275*) and c.1193C>T (pPro398Leu) in CYP7B1 gene. No other pathogenic variant in frequent ALS/FTD causative genes was found. The CYP7B1 gene seems, therefore, to be the third gene associated with the phenoconversion from HSP to ALS, after the recently described UBQLN2 and ERLIN2 genes. We therefore expand the phenotype associated with CYP7B1 biallelic mutations and make an assumption about a link between cholesterol dyshomeostasis and ALS/FTD.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Familia 7 del Citocromo P450/genética , Demencia Frontotemporal/genética , Mutación/genética , Paraplejía/genética , Esteroide Hidroxilasas/genética , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo
7.
Neurosci Lett ; 761: 136108, 2021 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-34256108

RESUMEN

Spastic paraplegias (SPGs) are a group of clinically and genetically heterogeneous neurodegenerative diseases. Mutations in 78 genes have been identified in autosomal dominant hereditary SPG (AD-HSP) and autosomal recessive hereditary SPG (AR-HSP). Compared to familial HSP, much less is known about the genetic and clinical profiles of sporadic SPGs. In this study, we have screened mutations for 18 sporadic SPGs or AR-HSP patients (mainly Northern Chinese) by whole-exome sequencing. We identified 12 mutations in five genes in 9 (50%) patients, including 9 novel ones: SPG5A/CYP7B1 (c.851C > A; c.122 + 2 T > G), SPG11/KIAA1840 (c.1735 + 3_ 1735 + 6del AAGT); SPG7/SPG7 (c.1454G > A; c.1892_ 1906dup GAGGACGGGCCTCGG); SPG39/PNPLA6 (c.1591G > A; c. 2990C > T); SPG15/ ZFYVE26 (c. 4804C > T; c. 4278 G > A). Among all the mutations, 7 were detected in the SPG5A and SPG11. Age at onset was significantly younger in cases with mutations (15.45 ± 6.78 years) than those without mutations (25.56 ± 10.90 years) (P = 0.03). Except for two cases with the SPG5A mutations, all cases presented with complicated SPGs. Three cases carrying mutations in SPG7, SPG15, SPG39 showed symptoms and signs of ataxia. One case carrying the homozygous c.259 + 2 T > C mutation in CYP7B1 showed serum parameters indicating liver impairment. Magnetic resonance imaging showed significantly thinned corpus callosum in cases with SPG11 and SPG15, but not in those with SPG5A, SPG7 or SPG39. In contrast, cerebellar atrophy was prominent in the SPG7 and SPG39 cases. These findings expand the spectrum of genetic, clinical and imaging features of sporadic SPG and AR-HSP, and have important implications in genetic counselling, molecular mechanisms and precise diagnosis of the disease.


Asunto(s)
Tasa de Mutación , Paraplejía Espástica Hereditaria/genética , Adolescente , Adulto , Cerebelo/diagnóstico por imagen , Cuerpo Calloso/diagnóstico por imagen , Familia 7 del Citocromo P450/genética , Femenino , Humanos , Hígado/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Proteínas/genética , Paraplejía Espástica Hereditaria/diagnóstico por imagen , Paraplejía Espástica Hereditaria/patología , Esteroide Hidroxilasas/genética
8.
J Neurogenet ; 35(2): 84-94, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33771085

RESUMEN

Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous neurodegenerative disorder, characterized by lower-limb spasticity and weakness. To date, more than 82 loci/genes (SPG1-SPG82) have been identified that contribute to the cause of HSP. Despite the use of next-generation sequencing-based methods, genetic-analysis has failed in the finding of causative genes in more than 50% of HSP patients, indicating a more significant heterogeneity and absence of a given phenotype-genotype correlation. Here, we performed whole-exome sequencing (WES) to identify HSP-causing genes in three unrelated-Iranian probands. Candidate variants were detected and confirmed in the probands and co-segregated in the family members. The phenotypic data gathered and compared with earlier cases with the same sub-types of disease. Three novel homozygous variants, c.978delT; p.Q327Kfs*39, c.A1208G; p.D403G and c.3811delT; p.S1271Lfs*44, in known HSP-causing genes including ENTPD1, CYP7B1, and ZFYVE26 were identified, respectively. Intra and interfamilial clinical variability were observed among affected individuals. Mutations in CYP7B1 and ZFYVE26 are relatively common causes of HSP and associated with SPG5A and SPG15, respectively. However, mutations in ENTPD1 are related to SPG64 which is an ultra-rare form of HSP. The research affirmed more complexities of phenotypic manifestations and allelic heterogeneity in HSP. Due to these complexities, it is not feasible to show a clear phenotype-genotype correlation in HSP cases. Identification of more families with mutations in HSP-causing genes may help the establishment of this correlation, further understanding of the molecular basis of the disease, and would provide an opportunity for genetic-counseling in these families.


Asunto(s)
Apirasa/genética , Proteínas Portadoras/genética , Familia 7 del Citocromo P450/genética , Paraplejía Espástica Hereditaria/genética , Esteroide Hidroxilasas/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Masculino , Mutación , Linaje , Fenotipo , Paraplejía Espástica Hereditaria/fisiopatología , Secuenciación del Exoma , Adulto Joven
9.
Dig Dis Sci ; 66(11): 3885-3892, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-33385262

RESUMEN

BACKGROUND: We encountered 7 Japanese patients with bile acid synthesis disorders (BASD) including 3ß-hydroxy-Δ5-C27-steroid dehydrogenase/isomerase (3ß-HSD) deficiency (n = 3), Δ4-3-oxosteroid 5ß-reductase (5ß-reductase) deficiency (n = 3), and oxysterol 7α-hydroxylase deficiency (n = 1) over 21 years between 1996 and 2017. AIM: We aimed to clarify long-term outcome in the 7 patients with BASD as well as long-term efficacy of chenodeoxycholic acid (CDCA) treatment in the 5 patients with 3ß-HSD deficiency or 5ß-reductase deficiency. METHODS: Diagnoses were made from bile acid and genetic analyses. Bile acid analysis in serum and urine was performed using gas chromatography-mass spectrometry. Clinical and laboratory findings and bile acid profiles at diagnosis and most recent visit were retrospectively obtained from medical records. Long-term outcome included follow-up duration, treatments, growth, education/employment, complications of treatment, and other problems. RESULTS: Medians with ranges of current patient ages and duration of CDCA treatment are 10 years (8 to 43) and 10 years (8 to 21), respectively. All 7 patients, who had homozygous or compound heterozygous mutations in the HSD3B7, SRD5B1, or CYP7B1 gene, are currently in good health without liver dysfunction. In the 5 patients with CDCA treatment, hepatic function gradually improved following initiation. No adverse effects were noted. CONCLUSIONS: We concluded that CDCA treatment is effective in 3ß-HSD deficiency and 5ß-reductase deficiency, as cholic acid has been in other countries. BASD carry a good prognosis following early diagnosis and initiation of long-term CDCA treatment.


Asunto(s)
Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Hiperplasia Suprarrenal Congénita/genética , Ácidos y Sales Biliares/biosíntesis , Ácido Quenodesoxicólico/uso terapéutico , Familia 7 del Citocromo P450/metabolismo , Oxidorreductasas/genética , Esteroide Hidroxilasas/metabolismo , Adolescente , Adulto , Niño , Familia 7 del Citocromo P450/genética , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Predisposición Genética a la Enfermedad , Humanos , Japón , Mutación , Esteroide Hidroxilasas/genética , Adulto Joven
10.
Ann Clin Transl Neurol ; 7(4): 486-496, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32202070

RESUMEN

OBJECTIVES: To investigate the clinical, electrophysiological, neuroimaging characteristics and genetic features of SPG5 in Taiwan. METHODS: Mutational analysis of the coding regions of CYP7B1 was performed by utilizing targeted resequencing analysis of the 187 unrelated Taiwanese HSP patients. The diagnosis of SPG5 was ascertained by the presence of biallelic CYP7B1 mutations. The SPG5 patients received clinical, electrophysiological, and neuroimaging evaluations. Disease severity was assessed by using the Spastic Paraplegia Rating Scale (SPRS) and the disability score. Two microsatellite markers as well as 18 single-nucleotide polymorphism (SNP) markers flanking CYP7B1 were genotyped to assess the founder effect of the CYP7B1 p.R112* mutation. RESULTS: Nineteen SPG5 patients from 17 families were identified. They typically presented an insidious onset progressive spastic paraparesis with proprioception involvement beginning at age 8 to 40 years. Their MRIs often showed white matter abnormalities in bilateral occipito-parietal regions, spinal cord atrophy, and mild cerebellar atrophy. Six different mutations in CYP7B1 were recognized, including three novel ones (p.N131Ifs*4, p.A295V, and p.L439R). CYP7B1 p.R112* was the most common mutation and present in 88.2% of the 17 SPG5 pedigrees. The patients with homozygous CYP7B1 p.R112* mutations had a milder clinical severity. Detailed haplotype analyses demonstrated a shared haplotype in the 25 individuals carrying at least one single allele of CYP7B1 p.R112*, suggesting a founder effect. INTERPRETATION: This study delineates the distinct clinical and genetic features of SPG5 in Taiwan and provides useful information for the diagnosis and management of SPG5, especially in patients of Chinese descent.


Asunto(s)
Encéfalo/patología , Familia 7 del Citocromo P450/genética , Propiocepción/fisiología , Paraplejía Espástica Hereditaria , Esteroide Hidroxilasas/genética , Adulto , Edad de Inicio , Anciano , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Paraplejía Espástica Hereditaria/epidemiología , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/patología , Paraplejía Espástica Hereditaria/fisiopatología , Taiwán/epidemiología , Adulto Joven
11.
J Mol Endocrinol ; 64(3): 165-179, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31990658

RESUMEN

Many sex differences in liver gene expression originate in the brain, depend on GH secretion and may underlie sex disparities in hepatic disease. Because epigenetic mechanisms may contribute, we studied promoter methylation and microRNA abundance in the liver, associated with expression of sexual dimorphic genes in mice with selective disruption of the dopamine D2 receptor in neurons (neuroDrd2KO), which decreases hypothalamic Ghrh, pituitary GH, and serum IGFI and in neonatally androgenized female mice which have increased pituitary GH content and serum IGFI. We evaluated mRNA levels of the female predominant genes prolactin receptor (Prlr), alcohol dehydrogenase 1 (Adh1), Cyp2a4, and hepatocyte nuclear transcription factor 6 (Hnf6) and the male predominant gene, Cyp7b1. Female predominant genes had higher mRNA levels compared to males, but lower methylation was only detected in the Prlr and Cyp2a4 female promoters. In neuroDrd2KO mice, sexual dimorphism was lost for all genes; the upregulation (feminization) of Prlr and Cyp2a4 in males correlated with decreased methylation of their promoters, and the downregulation (masculinization) of Hnf-6 mRNA in females correlated inversely with its promoter methylation. Neonatal androgenization of females evoked a loss of sexual dimorphism only for the female predominant Hnf6 and Adh1 genes, but no differences in promoter methylation were found. Finally, mmu-miR-155-5p, predicted to target Cyp7b1 expression, was lower in males in association with higher Cyp7b1 mRNA levels compared to females and was not modified in neuroDrd2KO or TP mice. Our results suggest specific regulation of gene sexually dimorphic expression in the liver by methylation or miRNAs.


Asunto(s)
Alcohol Deshidrogenasa/genética , Hidrocarburo de Aril Hidroxilasas/genética , Familia 2 del Citocromo P450/genética , Familia 7 del Citocromo P450/genética , Hormona del Crecimiento/farmacología , Factor Nuclear 6 del Hepatocito/genética , Receptores de Prolactina/genética , Esteroide Hidroxilasas/genética , Alcohol Deshidrogenasa/metabolismo , Animales , Hidrocarburo de Aril Hidroxilasas/metabolismo , Familia 2 del Citocromo P450/metabolismo , Familia 7 del Citocromo P450/metabolismo , Epigénesis Genética/efectos de los fármacos , Epigénesis Genética/fisiología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hormona del Crecimiento/metabolismo , Factor Nuclear 6 del Hepatocito/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Regiones Promotoras Genéticas/genética , Receptores de Prolactina/metabolismo , Caracteres Sexuales , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Esteroide Hidroxilasas/metabolismo
12.
Pediatr Neonatol ; 61(1): 75-83, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31337596

RESUMEN

BACKGROUND: Inborn errors of bile acid metabolism (IEBAM) cause rare but treatable genetic disorders that can present as neonatal cholestasis or neurological diseases. Without timely primary bile acid treatment, patients may develop liver failure early in life. This study aimed to analyze the types and treatment outcomes of IEBAM in Taiwanese infants and document the allele frequency of CYP7B1 hot spot mutations in the population. METHODS: Urine samples from patients with infantile intrahepatic cholestasis and suspected IEBAM were subjected to urinary bile acid analysis by gas chromatography-mass spectrometry (GC/MS). Genetic diagnoses were made using direct sequencing or next-generation sequencing. We also tested healthy control subjects for a probable hot spot point mutation of CYP7B1. RESULTS: Among the 75 patients with infantile intrahepatic cholestasis tested during 2000 -2016, three had ∆4-3-oxosteroid 5ß-reductase deficiency with AKR1D1 mutations, and three had oxysterol-7α-hydroxylase deficiency with CYP7B1 mutation. Two patients with ∆4-3-oxosteroid 5ß-reductase deficiency were successfully treated with cholic acid. The three unrelated infants with oxysterol 7α-hydroxylase deficiencies had the same p.R112X homozygous CYP7B1 mutation. Two had mild renal or neurological involvement. Among 608 healthy control subjects, the allele frequency of the heterozygous mutation for p.R112X was 2/1216 (0.16%). The only surviving patient with oxysterol 7α-hydroxylase deficiency recovered from liver failure after chenodeoxycholic acid (CDCA) treatment beginning at 3 months of age. CONCLUSION: Distinct types of IEBAM disease were found in the Taiwanese population. Patients with early diagnosis and early treatment had a favorable outcome. IEBAM prevalence rates may be higher than expected due to the presence of heterozygous mutations in the general population.


Asunto(s)
Ácidos y Sales Biliares/metabolismo , Familia 7 del Citocromo P450/genética , Errores Innatos del Metabolismo/genética , Mutación , Oxidorreductasas/genética , Esteroide Hidroxilasas/genética , Femenino , Humanos , Lactante , Masculino , Errores Innatos del Metabolismo/diagnóstico
13.
Cell Cycle ; 18(23): 3337-3350, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31599189

RESUMEN

Gallbladder cancer (GBC) is the common malignancy of the bile tract system with extremely poor clinical outcomes, owing to its metastatic property and intrinsic resistance to the first-line drugs. Although it is well-established that cholesterol abnormity contributes to gallstone formation, a leading risk factor for GBC, the link of cholesterol homeostasis with GBC has not been investigated. The present study systematically examined the genes implicated in cholesterol homeostasis, and revealed altered gene expressions of de novo cholesterol biosynthesis and sterol sulfonation (SULT2B1), reduced bile acid synthesis (CYP7B1 and CYP39A1) and impaired sterol efflux (ABCA1, ABCG5, LCAT, and CETP) in GBC tissues. Suppression of cholesterol biosynthesis by lovastatin inhibited GBC cell proliferation possibly through attenuating the DNA repair process. Further investigation revealed lovastatin sensitized GBC cells to cisplatin-induced apoptosis and suppressed the activation of CHK1, CHK2, and H2AX during DNA damage response. By using chemically distinct statins, HMGCR depletion or supplementing mevalonate, the product of HMGCR, we showed the inhibitory effects on DNA repair process of lovastatin were due to the blockage of the mevalonate pathway. Subcutaneous xenograft mice model suggested lovastatin promoted the therapeutic efficacy of cisplatin, and significantly prolonged the survival times of tumor-bearing mice. Moreover, HMGCR ablation repressed tumor growth in vivo, which can be rescued partially by restored expression of HMGCR, suggesting the on-target effects of lovastatin. Therefore, our study provides the clinical relevance of cholesterol homeostasis with GBC progression, and highlights a novel intervention of combined use of lovastatin and cisplatin for GBC.


Asunto(s)
Colesterol/genética , Cisplatino/efectos adversos , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Cálculos Biliares/tratamiento farmacológico , Transportador 1 de Casete de Unión a ATP/genética , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Animales , Apoptosis/efectos de los fármacos , Colesterol/biosíntesis , Proteínas de Transferencia de Ésteres de Colesterol/genética , Cisplatino/farmacología , Familia 7 del Citocromo P450/genética , Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Femenino , Neoplasias de la Vesícula Biliar/genética , Neoplasias de la Vesícula Biliar/patología , Cálculos Biliares/genética , Cálculos Biliares/patología , Xenoinjertos , Humanos , Masculino , Ratones , Fosfatidilcolina-Esterol O-Aciltransferasa/genética , Factores de Riesgo , Esteroide Hidroxilasas/genética , Sulfotransferasas/genética
14.
Endocrinology ; 160(10): 2485-2494, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31386147

RESUMEN

27-Hydroxycholesterol (27HC) is an abundant cholesterol metabolite and has detrimental effects on the cardiovascular system, whereas its impact on adiposity is not well known. In this study, we found that elevations in 27HC cause increased body weight gain in mice fed a high-fat/high-cholesterol diet in an estrogen receptor α-dependent manner. Regardless of diet type, body fat mass was increased by 27HC without changes in food intake or fat absorption. 27HC did not alter energy expenditure in mice fed a normal chow diet and increased visceral white adipose mass by inducing hyperplasia but not hypertrophy. Although 27HC did not augment adipocyte terminal differentiation, it increased the adipose cell population that differentiates to mature adipocytes. RNA sequencing analysis revealed that 27HC treatment of mice fed a normal chow diet induces inflammatory gene sets similar to those seen after high-fat/high-cholesterol diet feeding, whereas there was no overlap in inflammatory gene expression among any other 27HC administration/diet change combination. Histological analysis showed that 27HC treatment increased the number of total and M1-type macrophages in white adipose tissues. Thus, 27HC promotes adiposity by directly affecting white adipose tissues and by increasing adipose inflammatory responses. Lowering serum 27HC levels may lead to an approach targeting cholesterol to prevent diet-induced obesity.


Asunto(s)
Adipogénesis/efectos de los fármacos , Adiposidad/efectos de los fármacos , Grasas de la Dieta/efectos adversos , Hidroxicolesteroles , Obesidad/inducido químicamente , Animales , Familia 7 del Citocromo P450/genética , Familia 7 del Citocromo P450/metabolismo , Dieta Alta en Grasa/efectos adversos , Grasas de la Dieta/farmacología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Inflamación/inducido químicamente , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/efectos de los fármacos , Esteroide Hidroxilasas/genética , Esteroide Hidroxilasas/metabolismo
15.
Sci Rep ; 9(1): 10260, 2019 07 16.
Artículo en Inglés | MEDLINE | ID: mdl-31311983

RESUMEN

Cholesterol mediates its proliferative and metastatic effects via the metabolite 27-hydroxycholesterol (27-HC), at least in breast and endometrial cancer. We determined the serum lipoprotein profile, intratumoral cholesterol and 27-HC levels in a cohort of patients with well-differentiated papillary thyroid carcinoma (PTC; low/intermediate and high risk), advanced thyroid cancers (poorly differentiated, PDTC and anaplastic thyroid carcinoma, ATC) and benign thyroid tumors, as well as the expression of genes involved in cholesterol metabolism. We investigated the gene expression profile, cellular proliferation, and migration in Nthy-ori 3.1 and CAL-62 cell lines loaded with human low-density lipoprotein (LDL). Patients with more aggressive tumors (high-risk PTC and PDTC/ATC) showed a decrease in blood LDL cholesterol and apolipoprotein B. These changes were associated with an increase in the expression of the thyroid's LDL receptor, whereas 3-hydroxy-3-methylglutaryl-CoA reductase and 25-hydroxycholesterol 7-alpha-hydroxylase were downregulated, with an intratumoral increase of the 27-HC metabolite. Furthermore, LDL promoted proliferation in both the Nthy-ori 3.1 and CAL-62 thyroid cellular models, but only in ATC cells was its cellular migration increased significantly. We conclude that cholesterol and intratumoral accumulation of 27-HC promote the aggressive behavior process of PTC. Targeting cholesterol metabolism could be a new therapeutic strategy in thyroid tumors with poor prognosis.


Asunto(s)
Carcinoma Papilar/patología , LDL-Colesterol/sangre , Hidroxicolesteroles/metabolismo , Neoplasias de la Tiroides/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Carcinoma Papilar/genética , Carcinoma Papilar/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Colestanotriol 26-Monooxigenasa/genética , Familia 7 del Citocromo P450/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Hidroximetilglutaril-CoA Reductasas/genética , Sistema de Señalización de MAP Quinasas , Masculino , Persona de Mediana Edad , Fosfatidilinositol 3-Quinasas/metabolismo , Receptores de LDL/genética , Esteroide Hidroxilasas/genética , Serina-Treonina Quinasas TOR/metabolismo , Carcinoma Anaplásico de Tiroides/genética , Carcinoma Anaplásico de Tiroides/metabolismo , Carcinoma Anaplásico de Tiroides/patología , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Adulto Joven
16.
Biomolecules ; 9(4)2019 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-31013940

RESUMEN

Deficiency in cytochrome P450 (CYP) 7B1, also known as oxysterol 7α-hydroxylase, in humans leads to hereditary spastic paraplegia type 5 (SPG5) and in some cases in infants to liver disease. SPG5 is medically characterized by loss of motor neurons in the corticospinal tract. In an effort to gain a better understanding of the fundamental biochemistry of this disorder, we have extended our previous profiling of the oxysterol content of brain and plasma of Cyp7b1 knockout (-/-) mice to include, amongst other sterols, 25-hydroxylated cholesterol metabolites. Although brain cholesterol levels do not differ between wild-type (wt) and knockout mice, we find, using a charge-tagging methodology in combination with liquid chromatography-mass spectrometry (LC-MS) and multistage fragmentation (MSn), that there is a build-up of the CYP7B1 substrate 25-hydroxycholesterol (25-HC) in Cyp7b1-/- mouse brain and plasma. As reported earlier, levels of (25R)26-hydroxycholesterol (26-HC), 3ß-hydroxycholest-5-en-(25R)26-oic acid and 24S,25-epoxycholesterol (24S,25-EC) are similarly elevated in brain and plasma. Side-chain oxysterols including 25-HC, 26-HC and 24S,25-EC are known to bind to INSIG (insulin-induced gene) and inhibit the processing of SREBP-2 (sterol regulatory element-binding protein-2) to its active form as a master regulator of cholesterol biosynthesis. We suggest the concentration of cholesterol in brain of the Cyp7b1-/- mouse is maintained by balancing reduced metabolism, as a consequence of a loss in CYP7B1, with reduced biosynthesis. The Cyp7b1-/- mouse does not show a motor defect; whether the defect in humans is a consequence of less efficient homeostasis of cholesterol in brain has yet to be uncovered.


Asunto(s)
Encéfalo/metabolismo , Familia 7 del Citocromo P450/genética , Hidroxicolesteroles/metabolismo , Paraplejía Espástica Hereditaria/metabolismo , Esteroide Hidroxilasas/genética , Animales , Familia 7 del Citocromo P450/deficiencia , Hidroxicolesteroles/sangre , Masculino , Ratones , Paraplejía Espástica Hereditaria/sangre , Paraplejía Espástica Hereditaria/genética , Esteroide Hidroxilasas/deficiencia
17.
Intern Med ; 58(5): 719-722, 2019 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-30333426

RESUMEN

SPG5 is a rare subtype of autosomal recessive hereditary spastic paraplegia caused by a homozygous mutation in the oxysterol 7α-hydroxylase gene, CYP7B1. We describe the first Japanese patient with SPG5 with a novel mutation in the CYP7B1 gene. On exome sequencing, we identified a homozygous frameshift mutation, c.741delA, p.K247fs, in exon 3 of the CYP7B1 gene. The patient showed spastic paraparesis with white matter hyperintensities in the bilateral corona radiata and periventricular and subcortical regions on brain magnetic resonance imaging. The present study expands the mutation spectrum of CYP7B1 and provides an opportunity to study the genotype-phenotype correlation in SPG5.


Asunto(s)
Familia 7 del Citocromo P450/genética , Mutación del Sistema de Lectura , Paraplejía Espástica Hereditaria/genética , Esteroide Hidroxilasas/genética , Anciano , Encéfalo/diagnóstico por imagen , Progresión de la Enfermedad , Exoma/genética , Exones/genética , Femenino , Homocigoto , Humanos , Imagen por Resonancia Magnética/métodos , Paraplejía Espástica Hereditaria/diagnóstico por imagen , Secuenciación del Exoma/métodos
18.
J Korean Med Sci ; 33(51): e324, 2018 Dec 17.
Artículo en Inglés | MEDLINE | ID: mdl-30546280

RESUMEN

Oxysterol 7α-hydroxylase deficiency is a very rare liver disease categorized as inborn errors of bile acid synthesis, caused by CYP7B1 mutations. As it may cause rapid progression to end-stage liver disease even in early infancy, a high index of suspicion is required to prevent fatal outcomes. We describe the case of a 3-month-old boy with progressive cholestatic hepatitis and severe hepatic fibrosis. After excluding other etiologies for his early liver failure, we found that he had profuse urinary excretion of 3ß-monohydroxy-Δ5-bile acid derivatives by gas chromatography/mass spectrometry analysis with dried urine spots on filter paper. He was confirmed to have a compound heterozygous mutation (p.Arg388Ter and p.Tyr469IlefsX5) of the CYP7B1 gene. After undergoing liver transplantation (LT) from his mother at 4 months of age, his deteriorated liver function completely normalized, and he had normal growth and development until the current follow-up at 33 months of age. We report the first Korean case of oxysterol 7α-hydroxylase deficiency in the youngest infant reported to undergo successful living donor LT to date.


Asunto(s)
Familia 7 del Citocromo P450/genética , Fallo Hepático/terapia , Trasplante de Hígado , Esteroide Hidroxilasas/genética , Ácidos y Sales Biliares/análisis , Análisis Mutacional de ADN , Cromatografía de Gases y Espectrometría de Masas , Humanos , Lactante , Fallo Hepático/diagnóstico , Fallo Hepático/genética , Fallo Hepático/patología , Donadores Vivos , Masculino , Polimorfismo de Nucleótido Simple , República de Corea , Errores Congénitos del Metabolismo Esteroideo/diagnóstico , Errores Congénitos del Metabolismo Esteroideo/terapia
19.
PLoS One ; 13(7): e0199682, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29965978

RESUMEN

Stearoyl-CoA desaturase 1 (SCD1) catalyzes the rate limiting step in monounsaturated fatty acid synthesis by inserting a double bond at the delta-9 position of long-chain fatty acids. SCD1 converts stearate (18:0) to oleate (18:1n9) and palmitate (16:0) to palmitoleate (16:1n7), respectively. Mice with global and skin-specific deletion (SKO) of SCD1 exhibit increased whole body energy expenditure and protection against diet-induced adiposity, hepatic steatosis, insulin sensitivity and glucose intolerance. The mechanisms that link cutaneous lipid homeostasis with whole body energy balance are presently unknown. In this study, we reveal that SKO mice demonstrate increased skin surface free cholesterol, decreased circulating total cholesterol and increased taurine-conjugated and hydrophilic bile acids. Tauro-ß-muricholic acid, which is a marker of extrahepatic bile acid synthesis, is significantly elevated in SKO plasma. Bile acid signaling through the bile acid-specific receptor TGR5 is known to be protective against obesity and metabolic disease; a phenotype that is similar to SKO mice. We therefore examined TGR5 expression and its downstream mediator, DIO2, in various tissues and found that both TGR5 and DIO2 expression were significantly increased in brown adipose tissue. In sum, we suggest that skin-derived bile acids are involved in the lean and metabolically healthy phenotype of SKO mice.


Asunto(s)
Ácidos y Sales Biliares/sangre , Ácidos y Sales Biliares/química , Obesidad , Piel/enzimología , Estearoil-CoA Desaturasa/genética , Estearoil-CoA Desaturasa/metabolismo , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Animales , Biomarcadores , Colesterol/metabolismo , Familia 7 del Citocromo P450/genética , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Ratones , Ratones Noqueados , Especificidad de Órganos , Glándulas Sebáceas/metabolismo , Transducción de Señal , Esteatorrea/genética , Esteatorrea/metabolismo , Esteroide Hidroxilasas/genética , Termogénesis/genética
20.
Toxicol Lett ; 286: 48-53, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29357290

RESUMEN

There have been many concerns about the possible adverse effects of thyroid hormone-disrupting chemicals in the environment. Because thyroid hormones are essential for regulating the growth and differentiation of many tissues, disruption of thyroid hormones during the neonatal period of an organism might lead to permanent effects on that organism. We postulated that there are target genes that are sensitive to thyroid hormones particularly during the neonatal period and that would thus be susceptible to thyroid hormone-disrupting chemicals. Global gene expression analysis was used to identify these genes in the liver of rat neonates. The changes in hepatic gene expression were examined 24 h after administering 1.0, 10, and 100 ng/g body weight (bw) triiodothyronine (T3) to male rats on postnatal day 3. Thirteen upregulated and four downregulated genes were identified in the neonatal liver. Among these, Pdp2 and Slc25a25 were found to be upregulated and more sensitive to T3 than the others, whereas Cyp7b1 and Hdc were found to be downregulated even at the lowest dose of 1.0 ng/g bw T3. Interestingly, when the responses of gene expression to T3 were examined in adult rats (8-week old), one-third of them did not respond to T3. The environmental chemicals with thyroid hormone-like activity, hydroxylated polybrominated diphenyl ethers, were then administered to neonatal rats to examine the effects on expression of the identified genes. The results showed that these chemicals were indeed capable of changing the expression of Slc25a25 and Hdc. Our results demonstrated a series of hepatic T3-responsive genes that are more sensitive to hormones during the neonatal period than during adulthood. These genes might be the potential targets of thyroid hormone-disrupting chemicals in newborns.


Asunto(s)
Disruptores Endocrinos/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Hígado/efectos de los fármacos , Triyodotironina/farmacología , Animales , Animales Recién Nacidos , Familia 7 del Citocromo P450/genética , Familia 7 del Citocromo P450/metabolismo , Relación Dosis-Respuesta a Droga , Perfilación de la Expresión Génica/métodos , Histidina Descarboxilasa/genética , Histidina Descarboxilasa/metabolismo , Hígado/metabolismo , Masculino , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Piruvato Deshidrogenasa (Lipoamida)-Fosfatasa/genética , Piruvato Deshidrogenasa (Lipoamida)-Fosfatasa/metabolismo , Ratas Endogámicas F344 , Medición de Riesgo , Esteroide Hidroxilasas/genética , Esteroide Hidroxilasas/metabolismo
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