UGT1A1 dysfunction increases liver burden and aggravates hepatocyte damage caused by long-term bilirubin metabolism disorder.

UGT1A1 is the only enzyme that can metabolize bilirubin, and its encoding gene is frequently mutated. UGT1A1*6 (G71R) is a common mutant in Asia which leads to the decrease of UGT1A1 activity and abnormal bilirubin metabolism. However, it is not clear whether low UGT1A1 activity-induced bilirubin metabolism disorder increases hepatocyte fragility. ugt1a+/- mice were used to simulate the UGT1A1*6 (G71R) population. Under the same CCl4 induction condition, ugt1a+/- mice showed severer liver damage and fibrosis, indicating that ugt1a1 dysfunction increased liver burden and aggravated hepatocyte damage. In the animal experiment with a continuous intraperitoneal injection of bilirubin, the ugt1a+/- mice livers had more serious unconjugated bilirubin accumulation. The accumulated bilirubin leads to hyperphosphorylation of IκB-α, Ikk-ß, and p65 and a significant increase of inflammatory factor. The α-SMA and Collagen I proteins markedly up-regulated in the ugt1a+/- mice livers. Immunofluorescence and confocal microscopy showed that hepatic stellate cells and Kupffer cells were activated in ugt1a+/- mice. Comprehensive results show that there was a crosstalk relationship between low UGT1A1 activity-bilirubin-liver damage. Furthermore, cell experiments confirmed that unconjugated bilirubin activated the NF-κB pathway and induced DNA damage in hepatocytes, leading to the significant increase of inflammatory factors. UGT1A1 knockdown in hepatocytes aggravated the toxicity of unconjugated bilirubin. Conversely, overexpression of UGT1A1 had a protective effect on hepatocytes. Finally, Schisandrin B, an active ingredient with hepatoprotective effects, extracted from a traditional Chinese medicinal herb, which could protect the liver from bilirubin metabolism disorders caused by ugt1a1 deficiency by downregulating p65 phosphorylation, inhibiting Kupffer cells, reducing inflammation levels. Our data clarified the mechanism of liver vulnerability caused by cross-talk between low UGT1A1 activity bilirubin, and provided a reference for individualized prevention of liver fragility in Gilbert's syndrome.

Proton magnetic resonance spectroscopy of the anterior cingulate gyrus, insular cortex and thalamus in schizophrenia associated with idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome).

OBJECTIVE: To examine whether patients with schizophrenia associated with idiopathic unconjugated hyperbilirubinemia (Gilbert's syndrome [GS]) have specific changes in brain metabolism. METHODS: We applied proton magnetic resonance spectroscopy (H-MRS) to the anterior cingulate gyrus, insular cortex and thalamus of patients with schizophrenia and GS (n = 15) or without GS (n = 15), all diagnosed with schizophrenia according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), and healthy subjects (n = 20). RESULTS: In the anterior cingulate gyrus, patients with schizophrenia and GS showed significant decreases in N-acetyl aspartate/creatine-phosphocreatinine (NAA/Cr), choline/creatine-phosphocreatinine (Cho/Cr) and myoinositol/creatine-phosphocreatinine (ml/Cr) ratios compared with healthy subjects and compared with patients with schizophrenia without GS. Patients with schizophrenia without GS also showed significant decreases in NAA/Cr, Cho/Cr and ml/Cr compared with healthy subjects. In the insular cortex, patients with schizophrenia and GS showed significant decreases in NAA/Cr, Cho/Cr and ml/Cr compared with healthy subjects and compared with patients with schizophrenia without GS. Patients with schizophrenia without GS also showed significant decreases in NAA/Cr, Cho/Cr and ml/Cr compared with healthy subjects. In the thalamus, patients with schizophrenia and GS showed significant decreases in NAA/Cr, Cho/Cr and ml/Cr compared with healthy subjects, whereas patients with schizophrenia without GS only showed a significant decrease in ml/Cr compared with healthy subjects. CONCLUSIONS: Our findings suggest that brain metabolism is more severely compromised in the subtype of schizophrenia with GS.

Familial unconjugated hyperbilirubinemia syndromes.

Our understanding of the biochemical defects underlying the hepatic forms of congenital, unconjugated hyperbilirubinemias has been greatly enhanced over the past decade. This is mostly due to the availability of pure, labeled bilirubin, the appropriate kinetic analyses, and a better understanding of the mechanisms underlying bilirubin conjugation. Although it is quite obvious that the defect underlying Gilbert's and Crigler-Najjar syndromes is deficient glucuronidation, the molecular explanation may eventually be found in altered composition of the microsomal lipids rather than in a protein defect of glucuronyl transferase. The recognition that Gilbert's syndrome is a quite heterogeneous entity will allow a better understanding of the mode of inheritance of this disorder; its relationship to Crigler-Najjar type II disease also awaits further definition. It is hoped that definition of the molecular defect in Crigler-Najjar type I will lead to better therapeutic modalities, but this remains to be seen.