Generation of an Adult Hyperbilirubinemia Model in Liver‐specific Humanized UGT1A1*6 Mice

다국어 초록 (Multilingual Abstract)

Bilirubin is metabolized in liver by UDP‐glucuronosyltransferase 1A1 (UGT1A1). Genetic polymorphisms associated with the UGT1A1 gene are commonly known to be responsible for increased levels of total serum bilirubin (TSB). Variants in the UGT1A1 gene promoter as well as Single Nucleotide Polymorphisms (SNPs) at both promoter and exons can result in UGT1A1 deficiency and impairment of bilirubin conjugation, leading to an icterus condition (jaundice) or hereditary unconjugated hyperbilirubinemia. Gilbert Syndrome (GS) is a common heritable condition of adult hyperbilirubinemia affecting over 10% of the population. The most common polymorphisms are the TA‐insertion in the TATA box (TA7) sequence in the promoter region of the UGT1A1 gene. In addition, a SNP at nucleotide 211G>A (G71R) in exon 1 of the UGT1A1*6 gene confers adult hyperbilirubinemia or GS. To examine the contribution of the UGT1A1*6 gene (R71) towards adult hyperbilirubinemia, a UGT1A1*6 and a UGT1A1*1 (G71) cDNA was expressed specifically in the liver of Ugt1−/− mice. Adult humanized UGT1A1*6 mice (h1A1*6HEP mice) expressed an icteric condition compared to normal TSB levels in h1A1*1HEP mice. Differences in TSB levels between h1A1*1HEP and h1A1*6HEP mice was reflected in expression levels of liver UGT1A1. The elevated TSB levels in h1A1*6HEP mice was consistent with the h1A1*6HEP mice being leaner than h1A1*1HEP mice, linking elevated TSB levels and its antioxidant potential with reduced body fat. Functional studies using liver extracts confirmed that the Km for 7‐ethyl‐10‐hydroxy‐camptothecin (SN‐38) and bilirubin glucuronidation was similar for UGT1A1*1 and UGT1A1*6, while there was a significant decrease in the Vmax associated with UGT1A1*6. The reduced Vmax is associated with reduced liver UGT1A1*6 expression and elevated TSB levels. Reduced expression of UGT1A1*6 may explain in part the contribution of elevated TSB levels in GS.
Support or Funding Information
USPHS grants GM086713 and ES010337 and grant PJT‐148611
This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.