Introduction of the American Pediatric Society's 2006 John Howland Award recipient, Kurt Hirschhorn, M.D.
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Awards and Prizes↗
Biomedical subjects
Frederick J Suchy
Publications and source records attributed to Frederick J Suchy.
Identification of functionally relevant residues of the rat ileal apical sodium-dependent bile acid cotransporter.
The mechanisms underlying the transport of bile acids by apical sodium-dependent bile acid transporter (Asbt) are not well defined. To further identify the functionally relevant residues, thirteen conserved negatively (Asp and Glu) and positively (Lys and Arg) charged residues plus Cys-270 of rat Asbt were replaced with Ala or Gln by site-directed mutagenesis. Seven of the fourteen residues of rat Asbt were identified as functionally important by taurocholate transport studies, substrate inhibition assays, confocal microscopy, and electrophysiological methods. The results showed that Asp-122, Lys-191, Lys-225, Lys-256, Glu-261, and Lys-312,Lys-313 residues of rat Asbt are critical for transport function and may determine substrate specificity. Arg-64 may be located at a different binding site to assist in interaction with non-bile acid organic anions. For bile acid transport by Asbt, Na(+) ion movement is a voltage-dependent process that tightly companied with taurocholate movement. Asp-122 and Glu-261 play a critical role in the interaction of a Na(+) ion and ligand with Asbt. Cys-270 is not essential for the transport process. These studies provide new details about the amino acid residues of Asbt involved in binding and transport of bile acids and Na(+).
Animals↗
National and regional analysis of exceptions to the Pediatric End-Stage Liver Disease scoring system (2003-2004).
Since February 2002, the Pediatric End Stage Liver Disease (PELD) scoring system has been utilized as a means of prioritizing children for liver transplantation. The United Network for Organ Sharing database was queried to assess utilization of PELD in 2003 and 2004; 682 liver transplants were performed in pediatric recipients where the PELD score was potentially the primary determinant of liver allocation. In the majority of circumstances (53%) the actual calculated PELD score was not utilized to determine liver allocation. An exception to the PELD score was utilized in 24% of cases. An additional 29% of the children were listed as urgent (status 1) without having acute liver failure. There was considerable regional variability in the inability to utilize actual PELD scores for liver allocation to children. PELD utilization was higher in regions of the country where pediatric donor organs were more available, presumably because children have some priority for organs from pediatric donors. There were 87 deaths in children awaiting liver transplantation. The mean PELD score in children without acute liver failure or metabolic liver disease (n = 33) near the time of death was 24.2, which has a purported 3-month risk of mortality of less than 10%. In our opinion the assigned 3-month risk of mortality associated with PELD scores is understated. Three-month mortality risk is used to inter-convert the adult and pediatric scoring systems. Therefore exceptions to the scoring system are required when children compete with adults for donor organs. In conclusion, urgent reassessment of the PELD scoring system is needed to avoid morbidity and mortality in children.
Child↗
The hepatic fibrocystic diseases.
The hepatic fibrocystic diseases present with variable intrahepatic biliary abnormalities, which range from portal tract enlargement and fibrosis to cystic formations. They may present as autosomal recessive or dominant polycystic kidney diseases, with associated dilatation of the renal collecting system, or as incompletely characterized cystic diseases. Symptoms from the liver disease often result from complications of fibrosis or dilated ducts/cyst (sludge, lithiasis, infection). The treatment is supportive, with careful attention to associated renal disease. Liver transplantation is an option in selected patients.
Caroli Disease↗
Bile salt excretory pump: biology and pathobiology.
Bile acids are the major determinant and driving force for the generation of bile flow. Bile acid transport across the canalicular membrane is primarily an ATP-dependent process. The predominant transporter is the bile salt excretory pump (BSEP, ABCB11), a member of the adenosine triphosphate-binding cassette (ABC) family of transporters. Regulatory mechanisms that can coordinate the genes encoding bile acid transport proteins are critically important to avoid hepatocyte damage from intracellar accumulation of bile acids. Bile salts are natural ligands for several nuclear hormone receptors expressed in liver and intestine. Nuclear receptors are transcription factors that bind specific ligands such as bile acids and regulate gene expression according to the metabolic requirements of the cell. In cloning of the BSEP gene, we found a binding site in the promoter for the farnesoid X receptor (FXR), a nuclear receptor for bile acids. FXR activity requires heterodimerization with the 9-cis retinoid receptor (RXR alpha), and when bound by bile acids and retinoic acid, the complex effectively activates the transcription of BSEP. There is a growing body of evidence for the activation of nuclear hormone receptors through the remodeling of chromatin by histone modification involving acetylation, in concert with methylation of H3 and H4 histones. We have recently demonstrated a role for the coactivator-associated arginine methyltransferase 1 (CARM1), as a coactivator of the FXR/RXR receptor and regulator of FXR responsive genes such as BSEP. Chromatin immunoprecipitation showed that the bile acid-dependent activation of the human BSEP is associated with a simultaneous increase of FXR and CARM1 occupation of the BSEP promoter. The increased occupation of the BSEP locus by CARM1 also corresponds with the increased deposition of Arg-17 methylation and Lys-9 acetylation of histone H3 within the FXR DNA-binding element of BSEP. Our work on the role of nuclear receptors in regulation of bile acid homeostasis has led to an increased understanding of the pathogenesis of the disorder, progressive familial intrahepatic cholestasis, type 1 (PFIC1) or Byler disease. The gene mutated in PFIC1 is called FIC1 and codes for a type IV P-type ATPase whose function is unknown. Increased ileal apical sodium-dependent bile acid transporter messenger RNA (mRNA) expression was detected in 3 patients with PFIC1. Ileal FXR and short heterodimer partner (an inhibitory nuclear receptor) messenger RNA levels were reduced in the same 3 patients. In studies of cells after antisense-mediated knock-down of endogenous FIC1, the activity of the ileal apical bile acid transporter promoter was enhanced, whereas the activities of the human FXR and BSEP promoters were reduced. Nuclear but not cytoplasmic localization of FXR is markedly decreased in FIC1-negative cells, indicating that FIC1 is necessary for posttranslational modifications necessary for the nuclear translocation of FXR. This defect leads to enhanced ileal bile salt uptake and impaired canalicular bile salt secretion by BSEP. In PFIC1, an increased load of bile acids is retained in the liver leading to cholestasis and progressive liver injury.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Hepatitis C in children: a quaternary referral center perspective.
INTRODUCTION: Chronic hepatitis C virus (HCV) infection affects 0.3% of children in the United States, and the general impression is that it has a benign course in childhood. We analyzed a pediatric population with chronic HCV in a quaternary referral center. MATERIAL AND METHODS: This is a retrospective clinical review comprising all patients with chronic HCV referred to the Pediatric Liver/Liver Transplant Program between January 1999 and December 2004. RESULTS: Ninety-one patients (52% female; mean age, 9 years) were assessed. Eight-three percent of the patients were genotype 1. Twenty-one patients received/are receiving interferon and ribavirin for chronic HCV (treatment indications--advanced disease, 9; clinical trial, 6; genotype 2, 2; social, 2; prerenal transplant, 1). Eight (53%) of 15 patients, who have completed therapy and follow-up, achieved sustained viral response. Seven of 91 patients had cirrhosis at presentation (mean age, 11.7 years). Four underwent liver transplantation, all experienced HCV recurrence, 2 died, 1 was retransplanted, and 1 has compensated cirrhosis. CONCLUSION: Although, in general, HCV in children has a slow progression, there are cases with an accelerated course and early development of cirrhosis requiring liver transplant. Hepatitis C virus recurs universally after transplant, and its prognosis is usually poor; therefore, the most promising long-term approach is to clear this infection before transplantation.
Adolescent↗
Cytokine-dependent regulation of hepatic organic anion transporter gene transactivators in mouse liver.
Proinflammatory cytokines such as TNF-alpha and IL-1beta lead to downregulation of hepatic organic anion transporters in cholestasis. This adapted response is transcriptionally mediated by nuclear hormone receptors and liver-specific transcription factors. Because little is known in vivo about cytokine-dependent regulatory events, mice were treated with either TNF-alpha or IL-1beta for up to 16 h. Transporter mRNA expression was determined by Northern blot analysis, nuclear activity, and protein-expression of transactivators by EMSA and Western blotting. TNF-alpha induces a sustained decrease in Ntcp, Oatp1/Oatp1a1, and Bsep mRNA expression but exerts only transient [multidrug resistance-associated protein 2 (Mrp2)] or no effects (Mrp3) on Mrps. In addition to Ntcp and Oatp1/Oatp1a1, IL-1beta also downregulates Bsep, Mrp2, and Mrp3 mRNAs to some extent. To study transcriptional regulation, Ntcp and Bsep promoters were first cloned from mice revealing a new distal Ntcp hepatocyte nuclear factor 1 (HNF-1) element but otherwise show a conserved localization to known rat regulatory elements. Changes in transporter-expression are preceeded by a reduction in binding activities at IR-1, ER-8, DR-5, and HNF-1alpha sites after 4 h by either cytokine, which remained more sustained by TNF-alpha in the case of nuclear receptors. Nuclear protein levels of retinoid X receptor (RXR)-alpha are significantly decreased by TNF-alpha but only transiently affected by IL-1beta. Minor reductions of retinoic acid receptor, farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor nuclear proteins are restricted to 4 h after cytokine application and paralleled by a decrease in mRNA levels. Basolateral and canalicular transporter systems are downregulated by both cytokines, TNF-alpha and IL-1beta. Activity of HNF-1alpha as regulator of mNtcp is suppressed by both cytokines. Decreased binding activities of nuclear receptor heterodimers may be explained by a reduction of the ubiquitous heterodimerization partner RXR-alpha.
5' Untranslated Regions↗
Intrahepatic cholestasis: summary of an American Association for the Study of Liver Diseases single-topic conference.
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Bile Acids and Salts↗
Critical analysis of the pediatric end-stage liver disease scoring system: a single center experience.
The Pediatric End-Stage Liver Disease (PELD) scoring system is a new nationally utilized formula developed to provide a continuous numerical assessment of the risk of death in order to allocate livers to children for transplantation. A retrospective review of the clinical course of children undergoing liver transplantation at the Mount Sinai Medical Center was performed in order to assess the effectiveness of this scoring system in the first 24 months of its utilization. Forty-eight patients underwent liver transplantation with overall patient and graft survival rates of 98% and 96%, respectively. In 23 cases the PELD scoring system determined waiting time for transplantation. Of these 23 patients, 7 moved to the intensive care unit (ICU). Only 2 of 23 patients underwent transplantation with their actual PELD score. The rest required petition for exception (17) or status 1 listing (4). Significant morbidity occurred while awaiting transplantation: failure to thrive (78%), ascites (73%), hemorrhage (49%), infectious complications (39%), encephalopathy (30%), peritonitis (17%), pathologic bone fractures (13%), and hepatopulmonary syndrome (9%). In patients with PELD scores granted by exception the average score that did not yield a liver offer was 38 with an average waiting time of 55 days. At the time of transplantation actual PELD score averaged 22, while the petitioned score was 40. Based upon our center's initial experience, the current PELD scoring system is not adequate. Actual PELD scores did not lead to timely allocation of livers to children. It appears that this scoring system underestimates the near-term risk of death. Urgent reassessment is required to prevent potential morbidity and mortality in children. In conclusion the United Network for Organ Sharing policy that permits granting of exceptions has circumvented these problems with the PELD scoring system.
Adolescent↗
Role of CYP27A in cholesterol and bile acid metabolism.
The CYP27A gene encodes a mitochondrial cytochrome P450 enzyme, sterol 27-hydroxylase, that is expressed in many different tissues and plays an important role in cholesterol and bile acid metabolism. In humans, CYP27A deficiency leads to cerebrotendinous xanthomatosis. To gain insight into the roles of CYP27A in the regulation of cholesterol and bile acid metabolism, cyp27A gene knockout heterozygous, homozygous, and wild-type littermate mice were studied. In contrast to homozygotes, heterozygotes had increased body weight and were mildly hypercholesterolemic, with increased numbers of lipoprotein particles in the low density lipoprotein size range. Cyp7A expression was not increased in heterozygotes but was in homozygotes, suggesting that parts of the homozygous phenotype are secondary to increased cyp7A expression and activity. Homozygotes exhibited pronounced hepatomegaly and dysregulation in hepatic cholesterol, bile acid, and fatty acid metabolism. Hepatic cholesterol synthesis and synthesis of bile acid intermediates were increased; however, side chain cleavage was impaired, leading to decreased bile salt concentrations in gallbladder bile. Expression of Na-taurocholate cotransporting polypeptide, the major sinusoidal bile salt transporter, was increased, and that of bile salt export pump, the major canalicular bile salt transporter, was decreased. Gender played a modifying role in the homozygous response to cyp27A deficiency, with females being generally more severely affected. Thus, both cyp27A genotype and gender affected the regulation of hepatic bile acid, cholesterol, and fatty acid metabolism.
Animals↗
Ligand-dependent activation of the farnesoid X-receptor directs arginine methylation of histone H3 by CARM1.
In this study we demonstrate that the class II nuclear hormone receptor, farnesoid X-receptor (FXR), incorporates histone methyltransferase activity within the gene locus for bile salt export pump (BSEP), a well established FXR target gene that functions as an ATP-dependent canalicular bile acid transporter. This methyltransferase activity is directed specifically to arginine 17 of histone H3. We demonstrate that FXR is directly associated with co-activator-associated arginine methyltransferase 1 (CARM1) activity. Furthermore, we show by chromatin immunoprecipitation that the ligand-dependent activation of the human BSEP locus is associated with a simultaneous increase of FXR and CARM1 occupation. The increased occupation of the BSEP locus by CARM1 also corresponds with the increased deposition of Arg-17 methylation and Lys-9 acetylation of histone H3 within the FXR DNA-binding element of BSEP. Consistent with these findings, CARM1 led to increased BSEP promoter activity with an intact FXR regulatory element, whereas CARM1 failed to transactivate the BSEP promoter with a mutated FXRE. Induction of endogenous BSEP mRNA and Arg-17 methylation by FXR regulatory element ligand, CDCA, requires CARM1 activity. Therefore, histone methylation at Arg-17 by CARM1 is a downstream target of signaling through ligand-mediated activation of FXR. Our studies provide evidence that FXR directly recruits specific chromatin modifying activity of CARM1 necessary for full potentiation of the BSEP locus in vivo.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Multiple mechanisms of ontogenic regulation of nuclear receptors during rat liver development.
Nuclear receptors (NRs) play pivotal roles in the regulation of genes contributing to hepatobiliary cholesterol and bile acid homeostasis. We have previously shown that transporters involved in bile formation are developmentally regulated and are poorly developed during the fetal stage, but their expression reached gradual maturity during the postnatal period. To define the molecular mechanisms underlying this regulation and the role that class II NRs and associated members [liver receptor homolog-1 (LRH-1) and short heterodimer partner (SHP)] play, we have analyzed the ontogeny of NR expression during liver development. Real-time PCR analysis of hepatic NR expression from fetal day 17 through adult revealed that steady-state mRNA levels for all NRs were very low during the embryonic period. However, mRNA levels peaked close to that of adult rats (>6 wk-old rats) by 4 wk of age for farnesoid X receptor (FXR), pregnane X receptor (PXR), liver X receptor-alpha (LXRalpha), peroxisome proliferator-activated receptor-alpha (PPARalpha), retinoid acid receptor-alpha (RARalpha), LRH-1, and SHP, whereas RXRalpha mRNA lagged behind. FXR, PXR, LXRalpha, RARalpha, and PPARalpha functional activity in liver nuclear extracts assayed by gel EMSA demonstrated that the activity attained adult levels by 4 wk of age, exhibiting a strict correlation with mRNA levels. Surprisingly, PPARalpha activity was delayed as seen by EMSA assay. Protein levels for NRs also corresponded to the mRNA and functional activity except for RXRalpha. RXRalpha protein levels were higher than message levels, suggesting increased protein stability. We conclude that expression of NRs during rat liver development is primarily regulated by transcriptional mechanisms, which in turn, control the regulation of bile acid and cholesterol metabolic pathways.
Animals↗
Association of the 16-kDa subunit c of vacuolar proton pump with the ileal Na+-dependent bile acid transporter: protein-protein interaction and intracellular trafficking.
The rat ileal apical sodium-dependent bile acid transporter (Asbt) transports conjugated bile acids in a Na+-dependent fashion and localizes specifically to the apical surface of ileal enterocytes. The mechanisms that target organic anion transporters to different domains of the ileal enterocyte plasma membrane have not been well defined. Previous studies (Sung, A.-Q., Arresa, M. A., Zeng, L., Swaby, I'K., Zhou, M. M., and Suchy, F. J. (2001) J. Biol. Chem. 276, 6825-6833) from our laboratory demonstrated that rat Asbt follows an apical sorting pathway that is brefeldin A-sensitive and insensitive to protein glycosylation, monensin treatment, and low temperature shift. Furthermore, a 14-mer signal sequence that adopts a beta-turn conformation is required for apical localization of rat Asbt. In this study, a vacuolar proton pump subunit (VPP-c, the 16-kDa subunit c of vacuolar H+-ATPase) has been identified as an interacting partner of Asbt by a bacterial two-hybrid screen. A direct protein-protein interaction between Asbt and VPP-c was confirmed in an in vitro pull-down assay and in an in vivo mammalian two-hybrid analysis. Indirect immunofluorescence confocal microscopy demonstrated that the Asbt and VPP-c colocalized in transfected COS-7 and MDCK cells. Moreover, bafilomycin A1 (a specific inhibitor of VPP) interrupted the colocalization of Asbt and VPP-c. A taurocholate influx assay and membrane biotinylation analysis showed that treatment with bafilomycin A1 resulted in a significant decrease in bile acid transport activity and the apical membrane localization of Asbt in transfected cells. Thus, these results suggest that the apical membrane localization of Asbt is mediated in part by the vacuolar proton pump associated apical sorting machinery.
Animals↗
Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity.
BACKGROUND & AIMS: The mechanisms by which mutations in the familial intrahepatic cholestasis-1 gene cause Byler's disease (progressive familial intrahepatic cholestasis type 1) are unknown. METHODS: Interactions among the apical sodium-dependent bile acid transporter, the farnesoid X receptor (FXR), and familial intrahepatic cholestasis-1 were studied in the ileum of children with progressive familial intrahepatic cholestasis type 1 and in Caco-2 cells. RESULTS: Increased ileal apical sodium-dependent bile acid transporter messenger RNA (mRNA) expression was detected in 3 patients with progressive familial intrahepatic cholestasis type 1. Paradoxically, ileal lipid-binding protein mRNA expression was repressed, suggesting a central defect in bile acid response. Ileal FXR and short heterodimer partner mRNA levels were reduced in the same 3 patients. In Caco-2 cells, antisense-mediated knock-down of endogenous familial intrahepatic cholestasis-1 led to up-regulation of apical sodium-dependent bile acid transporter and down-regulation of FXR, ileal lipid-binding protein, and short heterodimer partner mRNA. In familial intrahepatic cholestasis-1-negative Caco-2 cells, the activity of the human apical sodium-dependent bile acid transporter promoter was enhanced, whereas the human FXR and bile salt excretory pump promoters' activities were reduced. Overexpression of short heterodimer partner but not of the FXR abrogated the effect of familial intrahepatic cholestasis-1 antisense oligonucleotides. FXR cis-element binding and FXR protein were reduced primarily in nuclear but not cytoplasmic extracts from familial intrahepatic cholestasis-1-negative Caco-2 cells. CONCLUSIONS: Loss of familial intrahepatic cholestasis-1 leads to diminished nuclear translocation of the FXR, with the subsequent potential for pathologic alterations in intestinal and hepatic bile acid transporter expression. Marked hypercholanemia and cholestasis are predicted to develop, presumably because of both enhanced ileal uptake of bile salts via up-regulation of the apical sodium-dependent bile acid transporter and diminished canalicular secretion of bile salts secondary to down-regulation of the bile salt excretory pump.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Neonatal cholestasis.
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Alagille Syndrome↗
FXR-mediated down-regulation of CYP7A1 dominates LXRalpha in long-term cholesterol-fed NZW rabbits.
We investigated how cholesterol feeding regulates cholesterol 7alpha-hydroxylase (CYP7A1) via the nuclear receptors farnesoid X receptor (FXR) and liver X receptor alpha (LXRalpha) in New Zealand white rabbits. After 1 day of 2% cholesterol feeding, when the bile acid pool size had not expanded, mRNA levels of the FXR target genes short-heterodimer partner (SHP) and sterol 12alpha-hydroxylase (CYP8B) were unchanged, indicating that FXR activation remained constant. In contrast, the mRNA levels of the LXRalpha target genes ATP binding cassette transporter A1 (ABCA1) and cholesteryl ester transfer protein (CETP) increased 5-fold and 2.3-fold, respectively, associated with significant increases in hepatic concentrations of oxysterols. Activity and mRNA levels of CYP7A1 increased 2.4 times and 2.2 times, respectively. After 10 days of cholesterol feeding, the bile acid pool size increased nearly 2-fold. SHP mRNA levels increased 4.1-fold while CYP8B declined 64%. ABCA1 mRNA rose 8-fold and CETP mRNA remained elevated. Activity and mRNA of CYP7A1 decreased 60% and 90%, respectively. Feeding cholesterol for 1 day did not enlarge the ligand pool size or change FXR activation, while LXRalpha was activated highly secondary to increased hepatic oxysterols. As a result, CYP7A1 was up-regulated. After 10 days of cholesterol feeding, the bile acid (FXR ligand) pool size increased, which activated FXR and inhibited CYP7A1 despite continued activation of LXRalpha. Thus, in rabbits, when FXR and LXRalpha are activated simultaneously, the inhibitory effect of FXR overrides the stimulatory effect of LXRalpha to suppress CYP7A1 mRNA expression.
ATP-Binding Cassette Transporters↗
Down-regulation of the Na+/taurocholate cotransporting polypeptide during pregnancy in the rat.
BACKGROUND: Experimental studies have shown decreased bile acid (BA) uptake and reduced excretion of cholephilic compounds in pregnant rodents. AIM: To assess the expression and function of the main BA importer, the Na(+)/taurocholate cotransporting polypeptide (Ntcp) in pregnant rats. METHODS: BA uptake and Ntcp expression were studied in control and timed-pregnant rats in late gestation. Ntcp protein, messenger RNA (mRNA) expression, and Ntcp tissue localization were determined by Northern blotting, Western analysis, and tissue immunofluorescence. The activity of three transactivators of the Ntcp promoter: hepatocyte nuclear factor 1-alpha (HNF1-alpha), nuclear receptor heterodimer retinoid X receptor:retinoid acid receptor (RXR:RAR) and signal transducer and activator of transcription 5 (Stat5) was assessed using gel electrophoretic mobility shift assays. RESULTS: A significantly reduced BA uptake and decreased Ntcp mRNA levels (-40%) and protein mass (-60%) was observed in pregnant rats. Nuclear extracts from pregnant rats showed a marked decrease of HNF1-alpha and RXR:RAR binding activities by -80 and -40% of basal activity, respectively. In contrast, binding activity of Stat-5 was increased by 50% in nuclear extracts from pregnant rats. CONCLUSIONS: Pregnancy is associated with reduced Ntcp expression and function in the rat. Our findings suggest that Ntcp down-regulation during pregnancy occurs primarily at the transcriptional level.
Animals↗
Differential developmental regulation of rat liver canalicular membrane transporters Bsep and Mrp2.
Bile formation depends on the active secretion of bile salts and other biliary constituents by specific transporters. Recently two major transporters that contribute to bile formation, the bile salt export pump (Bsep) and multidrug resistance protein-2 (Mrp2), have been cloned. The goal of the present study was to define the expression of Bsep and Mrp2 during rat liver development. mRNA expression as assessed by Northern blot and RT-PCR was higher for Mrp2 (40% of adult) at 21 d fetal age relative to Bsep (<20% of adult). The levels of Mrp2 mRNA increased to approximately 50% of adult at 1 d of life and then rapidly increased to adult levels by 1-3 wk. Nuclear run-on assays for Bsep and Mrp2 showed minimal transcription during fetal life with an increase in transcription in the postnatal period. A different pattern of expression was observed for both Mrp2 and Bsep proteins. During fetal life, there was low expression of Mrp2 and Bsep proteins (<20% of adult) with a gradual increase neonatally reaching adult levels at 4 wk. Thus, we noted a temporal delay between the maximal expression of the mRNA (1-3 wk) and protein (4 wk) for Bsep and Mrp2. These results show that 1) expression (of mRNA and protein) of canalicular transporters is developmentally regulated by both transcriptional and posttranscriptional mechanisms and 2) Mrp2 and Bsep gene expression (mRNA) are differentially regulated.
ATP Binding Cassette Transporter, Subfamily B, Mem↗