Histone Modifications Regulate the Developmental Expression of Human Hepatic UDP-Glucuronosyltransferase 1A1.

Human UDP-glucuronosyltransferase 1A1 (UGT1A1) is a unique enzyme involved in bilirubin conjugation. We previously characterized the hepatic expression of transcription factors affecting UGT1A1 expression during development. Accordingly, in this study, we characterized the ontogenetic expression of hepatic UGT1A1 from the perspective of epigenetic regulation. We observed significant histone-3-lysine-4 dimethylation (H3K4me2) enrichment in the adult liver and histone-3-lysine-27 trimethylation (H3K27me3) enrichment in the fetal liver, indicating that dynamic alterations of histone methylation were associated with ontogenetic UGT1A1 expression. We further showed that the transcription factor hepatocyte nuclear factor 1α (HNF1A) affects histone modifications around the UGT1A1 locus. In particular, we demonstrated that by recruiting HNF1A the cofactors mixed-lineage leukemia 1, the transcriptional coactivator p300, and nuclear receptor coactivator 6 aggregate at the UGT1A1 promoter, thereby regulating histone modifications and subsequent UGT1A1 expression. In this study, we proposed new ideas for the developmental regulation of metabolic enzymes via histone modifications, and our findings will potentially contribute to the development of age-specific therapies.

Hepatic expression of transcription factors affecting developmental regulation of UGT1A1 in the Han Chinese population.

PURPOSE: Complete or partial inactivity of UGT1A1, the unique enzyme responsible for bilirubin glucuronidation, is commonly associated with hyperbilirubinemia. We investigated the dynamic expression of UGT1A1, and that of the transcription factors (TFs) involved in its developmental regulation, during human hepatic growth in Han Chinese individuals. METHODS: Eighty-eight prenatal, pediatric, and adult liver samples were obtained from Han Chinese individuals. Quantitative real-time polymerase chain reaction was used to evaluate mRNA expression of UGT1A1 and TFs including PXR, CAR, HNF1A, HNF4A, PPARA, etc. UGT1A1 protein levels and metabolic activity were determined by western blotting and high-performance liquid chromatography. Direct sequencing was employed to genotype UGT1A1*6 (211G˃A) and UGT1A1*28 (TA6˃TA7) polymorphisms. RESULTS: UGT1A1 expression was minimal in prenatal samples, but significantly elevated during pediatric and adult stages. mRNA and protein levels and metabolic activity were prominently increased (120-, 20-, and 10-fold, respectively) in pediatric and adult livers compared to prenatal samples. Furthermore, expression did not differ appreciably between pediatric and adult periods. Dynamic expression of TFs, including PXR, CAR, HNF1A, HNF4A, and PPARA, was consistent with UGT1A1 levels at each developmental stage. A pronounced correlation between expression of these TFs and that of UGT1A1 (P < 0.001) was observed. Moreover, UGT1A1*6 and UGT1A1*28 polymorphisms reduced levels of UGT1A1 by up to 40-60 %. CONCLUSIONS: Hepatic expression of transcription factors is associated with developmental regulation of UGT1A1 in the Han Chinese population. Moreover, UGT1A1 polymorphisms are associated with reduced expression of UGT1A1 mRNA and protein, as well as enzyme activity.

[The randomized controlled trial of the treatment for clavicular fracture by rotatory manual reduction with forceps holder and retrograde percutaneous pinning transfixation].

OBJECTIVE: To study the curative effect and safety of rotatory manual reduction with forceps holder and retrograde percutaneous pinning transfixation in treating clavicular fracture. METHODS: All 201 cases of clavicular fractures were randomly divided into treatment group (101 cases) and control group (100 cases). The treatment group was treated by rotatory manual reduction with forceps holder and retrograde percutaneous pinning transfixation. The control group was treated by open reduction and internal fixation with Kirschner pin. All cases were followed up for 4 to 21 months (mean 10.6 months). SPSS was used to analyze clinic healing time of fracture and shoulder-joint function in both two groups. RESULTS: After operation, 101 cases of treatment group achieved union of fracture and the clinical healing time was 28 to 49 days (mean 34.5+/-2.7 days). In control group,there were 4 cases with nonunion of fracture,the other 96 cases were union,the clinical healing time was 36 to 92 days (mean 55.3+/-4.8 days). The excellent and good rate of shoulder-joint function was 100% in treatment group and 83% in control group. By t-test and chi2-test, there was significant difference between the two groups in curative effect (P<0.05). CONCLUSION: Rotatory manual reduction with forceps holder and retrograde pinning transfixation can be used in various kinds of clavicular shaft fracture, with many virtues such as easy operation, reliable fixation, short union time of fracture, good functional recovery of shoulder-joint and no incision scar affecting appearance.

[Percutaneous suture in the treatment of patellar fracture].

OBJECTIVE: To study therapeutic effects of patella and femur fixation combined with percutaneous suture in the treatment of patellar fractures. METHODS: In the study,23 patients with patellar fractures were treated with percutaneous Kirschner-pin transfixation and percutaneous suture after Kirschner pins transfixation of superior pole of patellar and condyle of femur. Among the patients, 17 patients were male and 6 patients were female, ranging in age from 18 to 73 years (mean 32.4 years). The therapeutic effects were evaluated according to Bistman criterion for patellar fracture. RESULTS: All the patients were followed up and ranged from 6 to 38 months (mean 11 months). All the fractures were anatomically reduction or near-anatomical reduction. According to Böstman criterion for patellar fracture, 20 were excellent and 3 good. CONCLUSION: The method of patella and femur fixation combined with suture for patellar fractures has such advantages as smaller invasion, less complication or sequel, fine reduction of fracture, good restoration of joint function and none operative cicatrix.