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Complete OATP1B1 and OATP1B3 deficiency underlies human Rotor syndrome.

ABSTRACT: Rotor syndrome is an autosomal recessive disorder characterized by conjugated hyperbilirubinemia, near-absent hepatic uptake of anionic diagnostics, and coproporphyrinuria. The mechanistic basis of other hyperbilirubinemia syndromes is largely understood, but that of Rotor syndrome has remained enigmatic. The existing paradigm of hepatic bilirubin excretion postulates a unidirectional elimination pathway: Uptake of conjugated bilirubin from blood by hepatocytes, glucuronidation of bilirubin, and excretion of conjugated bilirubin into bile by ABCC2, a canalicular bilirubin-glucuronide and xenobiotic export pump. An analogous view holds for drugs conjugated in the liver. Here we demonstrate by molecular-genetic analysis of 8 Rotor-syndrome families that Rotor syndrome is a two-gene disorder, with impaired hepatic re-uptake of bilirubin-glucuronide caused by complete deficiencies in the hepatic organic anion transporting polypeptides OATP1B1 and OATP1B3.

ORGANISM(S): Homo sapiens

PROVIDER: GSE33733 | GEO | 2012/01/16

SECONDARY ACCESSION(S): PRJNA148433

REPOSITORIES: GEO

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Project description:Neonatal hyperbilirubinemia (jaundice) is common in infants, with extremely preterm infants (EPT, <28 weeks gestational age) being at high risk for bilirubin-induced neurotoxicity, resulting in neurodevelopmental impairment. Hyperbilirubinemia is treated using phototherapy to lower unconjugated bilirubin levels. However, the benefits and risks of phototherapy in EPTs have not been well studied, and bilirubin at low levels may be protective as an antioxidant. Phototherapy is associated with markers of oxidative stress in the plasma, but the effects of phototherapy on the hippocampus (HPC) are not known. Bilirubin and insults associated with EPTs impair hippocampal development, a brain structure critical for cognitive function, but their underlying mechanisms remain unknown. The effects of hyperbilirubinemia and phototherapy on the HPC were studied using a Gunn rat model. Jaundiced (jj) and non-jaundiced (Nj) pups were subjected to phototherapy from postnatal day 4 (P4) through P6. The HPC was harvested and processed for RNA sequencing. Serum bilirubin levels were elevated in jj compared to Nj control rats. Phototherapy significantly lowered serum bilirubin levels in jj rats. Compared to Nj rats, 1294 genes were differentially expressed in the jj hippocampal transcriptome and mapped onto the nervous system development, inflammation, and ferroptosis signaling pathways. Phototherapy induces 3297 differentially-expressed genes (DEGs) in rat hippocampal transcriptome compared to untreated rats. These DEGs were annotated to pathways regulating synaptogenesis, long-term potentiation, and neurogenesis. Both hyperbilirubinemia and phototherapy altered expression of 407 genes, which mapped onto hippocampal plasticity functions, including neuritogenesis and long-term potentiation. Our study demonstrates a model for investigating molecular effects of hyperbilirubemia and phototherapy in an EPT-equivalent Gunn rat pup. Our data revealed the effects of hyperbilirubinemia and phototherapy on signaling pathways critical for hippocampal development and plasticity.

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Complete OATP1B1 and OATP1B3 deficiency underlies human Rotor syndrome.

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