Disruption of the Ugt1 Locus in Mice Resembles Human Crigler-Najjar Type I Disease

The 9 UDP-glucuronosyltranferases (UGTs) encoded by the UGT1 locus in humans are key enzymes in the metabolism of most drugs as well as endogenous substances such as bile acids, fatty acids, steroids, hormones, neurotransmitters, and bilirubin. Severe unconjugated hyperbilirubinemia in humans that suffer from Crigler-Najjar type I disease results from lesions in the UGT1A1 gene and is often fatal. To examine the physiological importance of the Ugt1 locus in mice, this locus was rendered non-functional by interrupting exon 4 to create Ugt1-/- mice. Because UGT1A1 in humans is responsible for 100% of the conjugated bilirubin, it followed that newborn Ugt1-/- mice developed serum levels of unconjugated bilirubin that were 40-60 times higher than Ugt1+/- or wild-type mice. The result of extreme unconjugated bilirubin in Ugt1-/- mice, comparable to the induced levels noted in patients with Crigler-Najjar type 1 disease, is fatal in neonatal Ugt1-/- mice within 2 weeks following birth. The extreme jaundice is present as a phenotype in skin color after 8 h. Neonatal Ugt1-/- mice exhibit no detectable UGT1A-specific RNA, which corresponds to a complete absence of UGT1A proteins in liver microsomes. Conserved glucuronidation activity attributed to the Ugt1 locus can be defined in Ugt1-/- mice, because UGT2-dependent glucuronidation activity is unaffected. Remarkably, the loss of UGT1A functionality in liver results in significant alterations in cellular metabolism as investigated through changes in gene expression. Thus, the loss of UGT1A function in Ugt1-/- mice leads to a metabolic syndrome that can serve as a model to further investigate the toxicities associated with unconjugated bilirubin and the impact of this disease in humans. The 9 UDP-glucuronosyltranferases (UGTs) encoded by the UGT1 locus in humans are key enzymes in the metabolism of most drugs as well as endogenous substances such as bile acids, fatty acids, steroids, hormones, neurotransmitters, and bilirubin. Severe unconjugated hyperbilirubinemia in humans that suffer from Crigler-Najjar type I disease results from lesions in the UGT1A1 gene and is often fatal. To examine the physiological importance of the Ugt1 locus in mice, this locus was rendered non-functional by interrupting exon 4 to create Ugt1-/- mice. Because UGT1A1 in humans is responsible for 100% of the conjugated bilirubin, it followed that newborn Ugt1-/- mice developed serum levels of unconjugated bilirubin that were 40-60 times higher than Ugt1+/- or wild-type mice. The result of extreme unconjugated bilirubin in Ugt1-/- mice, comparable to the induced levels noted in patients with Crigler-Najjar type 1 disease, is fatal in neonatal Ugt1-/- mice within 2 weeks following birth. The extreme jaundice is present as a phenotype in skin color after 8 h. Neonatal Ugt1-/- mice exhibit no detectable UGT1A-specific RNA, which corresponds to a complete absence of UGT1A proteins in liver microsomes. Conserved glucuronidation activity attributed to the Ugt1 locus can be defined in Ugt1-/- mice, because UGT2-dependent glucuronidation activity is unaffected. Remarkably, the loss of UGT1A functionality in liver results in significant alterations in cellular metabolism as investigated through changes in gene expression. Thus, the loss of UGT1A function in Ugt1-/- mice leads to a metabolic syndrome that can serve as a model to further investigate the toxicities associated with unconjugated bilirubin and the impact of this disease in humans. Jaundice is frequently observed and stems from a variety of hepatic and non-hepatic conditions such as infection, biliary obstruction, hemolysis, liver disease, and genetic diseases that influence hepatic metabolism and transport. It is symptomatic clinically by the accumulation of indirect or unconjugated bilirubin (UCB), 2The abbreviations used are: UCBunconjugated bilirubinUGTUDP-glucuronosyltransferaseCN1Crigler-Najjar type 1 disease4-MU4-methylum-billeferoneMPAmycophenolic acidTg-UGT1transgenic UGT1Bis-Tris2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diolT3triiodothyroxineT4thyroxineCYP7A1cholesterol 7α-hydroxylaseWTwild type. 2The abbreviations used are: UCBunconjugated bilirubinUGTUDP-glucuronosyltransferaseCN1Crigler-Najjar type 1 disease4-MU4-methylum-billeferoneMPAmycophenolic acidTg-UGT1transgenic UGT1Bis-Tris2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diolT3triiodothyroxineT4thyroxineCYP7A1cholesterol 7α-hydroxylaseWTwild type. which accumulates resulting in hyperbilirubinemia. The most benign genetic disease leading to hyperbilirubinemia is Gilbert syndrome, which is a common inheritable condition resulting in transient levels of UCB (1Bosma P.J. J. Hepatol. 2003; 38: 107-117Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). In humans, bilirubin is conjugated with glucuronic acid, which is catalyzed solely by UDP-glucuronosyltransferase (UGT) 1A1 (2Bosma P.J. Seppen J. Goldhoorn B. Bakker C. Oude E.R. Chowdhury J.R. Chowdhury N.R. Jansen P.L. J. Biol. Chem. 1994; 269: 17960-17964Abstract Full Text PDF PubMed Google Scholar). In Gilbert syndrome, hyperbilirubinemia is tied to a TA insertion in the promoter region of the UGT1A1 gene (3Monaghan G. Ryan M. Seddon R. Hume R. Burchell B. Lancet. 1996; 347: 578-581Abstract PubMed Scopus (492) Google Scholar, 4Bosma P.J. Chowdhury J.R. Bakker C. Gantla S. De Boer A. Oostra B.A. Lindhout D. Tytgat G.N.J. Jansen P.L.M. Elferink R.P.J.O. Chowdhury N.R. N. Engl. J. Med. 1995; 333: 1171-1175Crossref PubMed Scopus (1274) Google Scholar), characterized genetically as UGT1A1*28, and is felt to lead to reduced transcriptional activation of the gene and lowering of hepatic UGT1A1 levels. More detailed analysis of genetic variants associated with UGT1A1*28 indicate that Gilbert syndrome is part of a haplotype of four UGT1A variants spanning at least three UGT1A genes (5Lankisch T.O. Moebius U. Wehmeier M. Behrens G. Manns M.P. Schmidt R.E. Strassburg C.P. Hepatology. 2006; 44: 1324-1332Crossref PubMed Scopus (123) Google Scholar). The more serious of the genetic defects associated with UGT1A1 is Crigler-Najjar type 1 (CN1) disease (6Ritter J.K. Yeatman M.T. Ferreira P. Owens I.S. J. Clin. Invest. 1992; 90: 150-155Crossref PubMed Scopus (134) Google Scholar), an autosomal recessive syndrome where mutations in the coding region render the protein completely non-functional. The accumulation of UCB within focal brain regions leads to neural dysfunction followed by cell death and permanent disability (7Wennberg R.P. Cell Mol. Neurobiol. 2000; 20: 97-109Crossref PubMed Scopus (72) Google Scholar, 8Roger C. Koziel V. Vert P. Nehlig A. Early Hum. Dev. 1995; 43: 133-144Crossref PubMed Scopus (8) Google Scholar). If untreated by liver transplantation (9Sokal E.M. Silva E.S. Hermans D. Reding R. de Ville D.G. Buts J.P. Otte J.B. Transplantation. 1995; 60: 1095-1098Crossref PubMed Scopus (43) Google Scholar, 10Schauer R. Stangl M. Lang T. Zimmermann A. Chouker A. Gerbes A.L. Schildberg F.W. Rau H.G. J. Pediatr. Surg. 2003; 38: 1227-1231Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar), the complete inactivation of UGT1A1 in humans is fatal (11Crigler Jr., J.F. Najjar V.A. Pediatrics. 1952; 10: 169-180PubMed Google Scholar), and lethality is directly attributed to toxic concentrations of UCB. unconjugated bilirubin UDP-glucuronosyltransferase Crigler-Najjar type 1 disease 4-methylum-billeferone mycophenolic acid transgenic UGT1 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol triiodothyroxine thyroxine cholesterol 7α-hydroxylase wild type. unconjugated bilirubin UDP-glucuronosyltransferase Crigler-Najjar type 1 disease 4-methylum-billeferone mycophenolic acid transgenic UGT1 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol triiodothyroxine thyroxine cholesterol 7α-hydroxylase wild type. The UGT1A1 gene is part of the UGT1 locus (12Ritter J.K. Chen F. Sheen Y.Y. Tran H.M. Kimura S. Yeatman M.T. Owens I.S. J. Biol. Chem. 1992; 267: 3257-3261Abstract Full Text PDF PubMed Google Scholar), which encodes nine functional UGT1A proteins (13Gong Q.H. Cho J.W. Huang T. Potter C. Gholami N. Basu N.K. Kubota S. Carvalho S. Pennington M.W. Owens I.S. Popescu N.C. Pharmacogenetics. 2001; 11: PubMed Scopus Google Scholar), a in the metabolism of as well as endogenous substances such as fatty acids, bile acids, hormones, steroids, neurotransmitters, and bilirubin Strassburg C.P. 2000; PubMed Scopus Google Scholar). The of the UGT1 locus 2 is encoded by of with four at the and by an of nine that the of UGT1A Thus, the UGT1 locus encodes nine functional UGT1A of a region encoded by of the an encoded by UGT1A gene is from C.P. Manns M.P. Mol. PubMed Scopus Google Scholar, C.P. N. Manns M.P. Mol. Google Scholar, C.P. N. Manns M.P. Full Text Full Text PDF PubMed Scopus Google Scholar), which is to be the of glucuronidation of transgenic mice that the UGT1 locus S. D. N. U. R.P. J. J.K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google that the UGT1A genes can be in a to that observed in In the UGT1A genes are by the S. D. N. U. R.P. J. J.K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), the Chen S. U. J. J. R.P. J.K. PubMed Scopus Google Scholar), the liver M. J. J. J. B. P. Hepatology. 2006; 44: PubMed Scopus Google Scholar), as well as the S. D. N. U. R.P. J. J.K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the activation of by an J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), the UGT1A1 gene for and to the of endogenous for glucuronidation such as bilirubin. jaundice and hyperbilirubinemia can lead to toxicities associated with the of functional UGT1A1 Strassburg C.P. Mol. PubMed Scopus Google as well as or brain G. J. Pediatr. 2006; PubMed Scopus Google Scholar), that used to examine the and physiological conditions associated with defects in the gene or the Ugt1 the model a genetic in the Ugt1 locus T. J. Biol. Chem. Full Text PDF PubMed Google Scholar, M. Chowdhury J.R. Jansen P.L.M. M. Chowdhury N.R. J. Biol. Chem. Full Text PDF PubMed Google and hyperbilirubinemia J. Med. Google Scholar, J.R. R. Chowdhury N.R. Med. Google Scholar), the are to To the functional of the Ugt1 locus in mice, a model in which the coding region of exon 4 are complete of the Ugt1 locus in Ugt1-/- mice leading to levels of UCB that to comparable observed in patients with The absence of functional UGT1A protein neonatal mice to fatal associated with unconjugated hyperbilirubinemia. of the Ugt1-/- from a was by the with a to of the P. 1994; PubMed Scopus Google Scholar). exon 1 through exon with this that and the by interrupting of exon 4 the with the The was and the of the and of with were by after the as in of the were for were were to to that were to Ugt1-/- mice. was with and by were with to and for were by the and at the of was from neonatal mice by and to for in the at for serum was to bilirubin were for bilirubin and and at the a with and levels with a and were were as S. D. N. U. R.P. J. J.K. J. Biol. Chem. 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Clin. PubMed Scopus Google result in UCB levels that which corresponds to a in the indirect bilirubin levels In from Ugt1+/- that were at and from which serum was for UCB levels from Ugt1-/- mice were to more than in or Ugt1+/- mice The levels of UCB in mice from to in to in Ugt1-/- mice. The in bilirubin results from the accumulation of UCB. were no in or indirect bilirubin levels and Ugt1+/- mice. of liver such as serum and were in Ugt1-/- mice with serum is no of biliary or bilirubin in a The Ugt1 in Ugt1-/- from and mice, were from neonatal mice for analysis an UGT1A that was the region of UGT1A1 and to UGT1A proteins C. M. G. A. PubMed Scopus Google Scholar). analysis that the UGT1A with liver proteins from and mice, that the UGT1A proteins were no detectable UGT1A proteins in liver from Ugt1-/- mice. an was a proteins were in from and mice. The of proteins was by of the Ugt1 analysis of UGT1A defined the complete of UGT1A such as UGT1A1 and In UGT1A1 and gene are PubMed Scopus Google and in Ugt1+/- and mice as well as in In analysis a to exon of the Ugt1 locus that the of the Ugt1 locus leads to the complete absence of UGT1A-specific of UGT1A protein and in Ugt1+/- mice that at the Ugt1 locus can be by a in and protein with mice at the of analysis liver to UGT1A1 and UGT1A1 in Ugt1+/- and mice. was and used to The in 1 was used to the of UGT1A in liver of Ugt1+/- and Ugt1-/- The complete absence of proteins in Ugt1-/- mice was further investigated by of liver activity with and endogenous and In and are the UGT1A C.P. Manns M.P. Mol. PubMed Scopus Google Scholar). In and are the UGT1A that are PubMed Scopus Google Scholar). activity bilirubin as a was in Ugt1-/- mice, it was comparable in and Ugt1+/- mice. is conjugated by UGT1A proteins A.L. J. F. 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S. 2000; PubMed Scopus Google Scholar), are induced in Ugt1-/- mice, to the induced levels of of the I model developed by a genetic the common exon 4 of the Ugt1 locus that physiological conditions to is observed in Neonatal Ugt1-/- mice levels of UCB that results in death within 2 weeks following birth. The of the in exon 4 leads to a complete absence of UGT1A and to is observed in a The accumulation of UCB resulting from hyperbilirubinemia is attributed to the of the UGT1A1*28 which is to Gilbert syndrome, or mutations in of the UGT1A1 that results in or disease (1Bosma P.J. J. Hepatol. 2003; 38: 107-117Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). Crigler-Najjar type 2 is resulting from mutations or of and and is by or the UGT1A1 gene with Jr., J.F. J. Clin. Invest. PubMed Scopus Google Scholar). More lesions are associated with an of metabolism disease that results in mutations or and the UGT1A1 gene or the UGT1 locus non-functional. of exon 4 in Ugt1-/- mice the Ugt1 locus resulting in neonatal the in The most phenotype in the Ugt1-/- mice is neonatal jaundice and serum UCB levels that from to neonatal indirect bilirubin bilirubin in humans that are to in Strassburg C.P. 2000; PubMed Scopus Google to brain following the accumulation of bilirubin in the and at this to examine the impact of the hyperbilirubinemia in Ugt1-/- mice. The of UGT1A1 as the in bilirubin glucuronidation in humans in patients with through of mutations in the exon of the UGT1A1 gene (2Bosma P.J. Seppen J. Goldhoorn B. Bakker C. Oude E.R. Chowdhury J.R. Chowdhury N.R. Jansen P.L. J. Biol. 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The most is in the of the with the accumulation of UCB in no impact neonatal or the of the to In the associated with of exon 4 in Ugt1-/- mice to the toxic associated with UCB leading to death within observed a 2 in serum bilirubin from that in this be in Ugt1-/- mice to and in It that levels in are to after by at following T. S. M. S. T. S. J. Invest. PubMed Scopus Google Scholar). In with this liver glucuronidation activity in is with that observed in and M. Scholar). liver glucuronidation is completely in Ugt1-/- mice, which to levels of at the levels of and are in Ugt1-/- and Ugt1+/- mice, that the influence of glucuronidation is by of the Ugt1 locus in neonatal mice. as a for the J. M. R. U. S. A. 2003; PubMed Scopus Google as well as the D. PubMed Scopus Google Scholar). In bilirubin the as by the of the to to In levels of and protein and are in liver of neonatal J. Mol. 43: Google Scholar). In mice, that neonatal to through leads to activation of the and of activity in transgenic mice, that activation of the can in mice. Thus, bilirubin as an endogenous in Ugt1-/- mice, to of the at following and at levels of UCB in is no detectable or in protein in Ugt1-/- mice with that were or for the Ugt1 In neonatal of as by analysis is in Ugt1-/- mice, that the of in neonatal mice is most a in of genes by bilirubin. of that drugs or can be used as to the of of the UGT1A of of in to the is for the glucuronidation of S. 2003; PubMed Scopus Google Scholar). is with the a significant in glucuronidation is is with M. J. A. M. PubMed Scopus Google Scholar). the that the of in the and or J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google with a that can M. J. A. M. PubMed Scopus Google Scholar). it is this with is in in mice. is a in glucuronidation activity and Ugt1-/- mice. result leads to that is to is a protein More this result that proteins a in the glucuronidation of and indicate that is a or to the of expression. the associated with hyperbilirubinemia to result in analysis of gene in from Ugt1-/- mice to that the result from cellular and alterations that are in of the most significant changes with genes that are for cell Neonatal liver is and a of genes tied to the of cell are significant changes were noted with fatty acid and changes in gene were attributed in part to genes to such as the because tied to metabolism and the which a in acid metabolism J.R. J. 1992; PubMed Scopus Google Scholar). of the genes such as are the of to of and It is to that neonatal Ugt1-/- mice to be as by with and Ugt1+/- The UGT1 locus to be in transgenic mice in a that that in S. D. N. U. R.P. J. J.K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a significant of the UGT1A proteins accumulates in the and of mice S. D. N. U. R.P. J. J.K. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Chen S. U. J. J. R.P. J.K. PubMed Scopus Google Scholar), to observed in is genes are in associated with glucuronidation such as to and a model to the of glucuronidation as it to and in of and the to Ugt1+/- mice with mice, can be with mice to examine the of glucuronidation as it to by by and in metabolism and

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