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Biomedical subjects

Michael Fried

Publications and source records attributed to Michael Fried.

At least 19 recordsLinked to original sources
PubMed2006

Analysis of risk factors for low bone mineral density in inflammatory bowel disease.

BACKGROUND/AIM: Several risk factors have been suggested for osteoporosis which frequently occurs in inflammatory bowel disease (IBD) patients. We studied prevalence and risk factors for reduced bone mineral density (BMD) in IBD patients at the University Hospital of Zurich, Switzerland. METHODS: The BMD was determined by dual-energy X-ray absorptiometry at the lumbar spine and femoral neck in 88 IBD patients (55 with Crohn's disease, 30 with ulcerative colitis, and 3 with indeterminate colitis). Z scores were obtained by comparison with age- and sex-matched normal values, and T scores by comparison with sex-matched healthy young adults. Osteopenia and osteoporosis were defined according to the WHO guidelines. Predictive factors for BMD were analyzed by group comparison and stepwise regression analysis. RESULTS: Osteopenia was present in 43% of the patients at the lumbar spine and in 42% of them at the femoral neck. Osteoporosis was present in 14% of the patients at the lumbar spine and in 5% of them at the femoral neck. At the lumbar spine, stepwise regression analysis showed that body mass index, age, number of bowel resections, topic steroids, and azathioprine correlated with the Z scores. Cumulative steroid dose, topic steroids, age and bowel resection were found to be predictors for a pathological T score. At the femoral neck, regression analysis showed that body mass index, age, topic steroids, and azathioprine correlated with the Z scores. Only a low body mass index was a significant predictor for pathological femoral T scores. CONCLUSIONS: Osteopenia and osteoporosis are commonly found in IBD patients. Steroid treatment and bowel resection were significant risk factors for osteoporosis of the lumbar spine. However, disease-inherent factors also appear to confer a major risk, indicating that the BMD should be determined in all IBD patients, irrespective of steroid treatment.

Absorptiometry, Photon↗
PubMed2006

Gastric motor function and emptying in the right decubitus and seated body position as assessed by magnetic resonance imaging.

PURPOSE: To determine the effect of the right decubitus lying body position (RP) on relevant parameters of human gastric motor function in healthy volunteers. MATERIALS AND METHODS: Postprandial gastric function after ingestion of a solid/liquid meal (150 g/150 mL) was assessed over 90 minutes in volunteers in the RP and seated position (SP). Ten healthy volunteers were imaged using two MRI systems that differed in architecture and field strength. Stomach and intragastric air volume, intragastric meal distribution, gastric emptying, and gastric peristalsis were compared between the RP and SP. RESULTS: Body position did not affect gastric relaxation (RP, 372 mL vs. SP, 384 mL) and initial gastric volumes (stomach: RP, 458 mL vs. SP, 462 mL; meal: RP, 377 mL vs. SP, 399 mL; intragastric air: RP, 110 mL vs. SP, 98 mL). Postprandial stomach volume and gastric activity (RP and SP, 3.1 minute(-1)) were also similar. Meal emptying showed different characteristics, resulting in a significant but small difference in meal volume of -43 mL at t = 90 minutes (P < 0.05). CONCLUSION: Gastric MRI in RP is feasible for clinical research assessing gastric motor function. The subtle difference in meal emptying may be induced by posture-dependent vagal activity. This study confirms that MRI is a highly sensitive imaging technique for assessing gastrointestinal function in humans.

Adult↗
PubMed2006

Protective antibody levels and dose requirements for IV 5% Nabi Hepatitis B immune globulin combined with lamivudine in liver transplantation for hepatitis B-induced end stage liver disease.

Lamivudine combined with Hepatitis B immune globulin (HBIg) prevents post liver transplant (LT) HBV recurrence. The study was designed to assess the impact of lamivudine on hepatitis B antibody (anti-HBs) and dosage requirements of intravenous 5% HBIg (Nabi-HB) in the first 36 weeks post LT. Adults undergoing LT for chronic HBV received lamivudine prior to or at LT, and IV HBIg 20,000 IU on day of LT, 10,000 on days 1-7, weeks 4 and 8, and 5,000 every 4 weeks thereafter. Replicative status based on serum HBV DNA (> 5 pg/mL = replicator (R) or < or = 5 pg/mL = nonreplicator (N) was determined at initiation of lamivudine (R or N) and within 2 weeks of LT (r or n), resulting in 3 groups: Nn, Rn, and Rr. Between December 1999 and May 2001, 30 patients (10 Nn, 13 Rn, 6 Rr, and 1 unknown), mean age of 52 years underwent LT. HBsAg neutralization was achieved with anti-HBs > 300 IU/L during week 1 and > 200 IU/L during weeks 2-12. All but one patient were HBsAg-negative on last follow-up. Pre-LT suppression of HBV replication resulted in similar dose requirements and pK in the Rn and Nn groups within 1 week after LT. Comparatively, the Rr group had greater HBIg requirements during weeks 1-12 due to greater anti-HBs clearance and shortened t(1/2) during the entire 36-week follow-up. In conclusion, this study provides a rationale for the use of lower HBIg doses in HBV patients with suppressed replication undergoing LT.

Adult↗
PubMed2006

Barostat measurement of rectal compliance and capacity.

PURPOSE: Fecal continence requires relaxation of the rectal wall and a reservoir of adequate capacity. Rectal compliance provides an assessment of rectal wall stiffness; however, compliance is also affected by rectal capacity. We developed and validated a barostat measurement of rectal capacity. By accounting for variation in rectal capacity, we aimed to improve the inconsistent relationship between rectal compliance, sensation, and continence reported in the literature. METHOD: Barostat measurements of rectal compliance and capacity were validated in 41 healthy, continent subjects. Slow staircase (0-40 mmHg) and rapid phasic (12-40 mmHg) distentions were performed on two separate days, filling sensations were assessed by visual analog score. A stool substitute retention test of rectal filling sensation and continence was performed. RESULTS: Variance of volume measurements decreased with pressure comparing conditioning vs. index distentions, staircase vs. phasic distentions, and measurements on different days (all P < 0.001). Correction for rectal capacity measured at 40 mmHg reduced the "normal range" of compliance measurements (P < 0.01) but not vice versa. Compared with unadjusted volume measurements, normalized rectal volume (percentage filling relative to rectal capacity) improved the description of rectal sensation visual analog score (P < 0.01). Rectal capacity correlated with filling sensations and the volume retained on retention testing (P < 0.01). CONCLUSION: Barostat measurements of rectal capacity at 40 mmHg are highly reproducible and not affected by distention protocol. The assessment of rectal capacity complements that of rectal compliance. Correction for rectal capacity provides an assessment of rectal wall stiffness independent of rectal geometry and improves the association of barostat volume measurements with rectal sensitivity and continence.

Adult↗
PubMed2005

The human organic anion transporter 2 gene is transactivated by hepatocyte nuclear factor-4 alpha and suppressed by bile acids.

The human organic anion transporter 2 (hOAT2, SLC22A7) mediates the sodium-independent uptake of numerous drugs, including cephalosporins, salicylates, dicarboxylates, and prostaglandins, and is mainly expressed in hepatocytes. Because the regulation of hOAT2 expression is poorly understood, we characterized cis-acting elements in the 5'-flanking region that regulate hOAT2 transcription. A consensus binding motif for the hepatocyte nuclear factor-4 alpha (HNF-4 alpha), arranged as a direct repeat (DR)-1, is located at nucleotides -329/-317 relative to the transcription initiation site. This element specifically binds HNF-4 alpha in electrophoretic mobility shift assays. A luciferase-linked hOAT2 promoter fragment containing the HNF-4 alpha binding site was transactivated upon cotransfection of an HNF-4 alpha expression vector in Huh7 cells, whereas site-directed mutagenesis of the DR-1 element abolished activation by HNF-4 alpha. Short interfering RNAs inhibiting endogenous HNF-4 alpha expression markedly reduced endogenous expression of hOAT2 in Huh7 cells. Because HNF-4 alpha is a known target for bile acid-mediated repression of gene transcription, we studied whether chenodeoxycholic acid (CDCA) suppresses hOAT2 gene expression by inhibiting HNF-4 alpha-mediated transactivation. Treatment of Huh7 cells with CDCA or the synthetic farnesoid X receptor (FXR) agonist GW4064 decreased mRNA and protein levels and also nuclear binding activity of HNF-4 alpha. The FXR-inducible transcriptional repressor small heterodimer partner inhibited transactivation of hOAT2 promoter constructs and of endogenous hOAT2 expression by HNF-4 alpha. We conclude that the hOAT2 gene is critically dependent on HNF-4 alpha and that bile acids repress the hOAT2 gene by inhibiting HNF-4 alpha. Hepatic uptake of hOAT2 substrates may thus be decreased in disease conditions associated with elevated intracellular levels of bile acids.

Base Sequence↗
PubMed2005

Effect of ingestion order of the fat component of a solid meal on intragastric fat distribution and gastric emptying assessed by MRI.

PURPOSE: To develop an MRI technique to investigate how varying the ingestion order of nonfat and fat components of a solid meal influences three-dimensional intragastric distribution and gastric emptying (GE). MATERIALS AND METHODS: Eight healthy subjects were studied twice in randomized order. On one occasion (condition F-NF), the fat component (40 g mayonnaise on toast) was served before the nonfat component (270 g pasta, 200 g tomato sauce, 100 mL water); on the other (condition NF-F), the ingestion order was reversed. GE and intragastric distribution of both components were assessed by MRI for 180 minutes. RESULTS: During condition F-NF, GE of fat was significantly faster than during condition NF-F (T(25) [min]: F-NF: 20 +/- 9; NF-F: 40 +/- 7; P < 0.05), a larger amount of fat was observed in the antrum during condition F-NF, and more fat layering occurred. No differences were observed in total GE between the two conditions. CONCLUSION: Meal ingestion order influences GE and intragastric distribution of fat, which can be assessed by MRI techniques, providing new insights into the physiology of gastric processing and intragastric distribution of different meal phases.

Adult↗
PubMed2005

The effects of loperamide on continence problems and anorectal function in obese subjects taking orlistat.

UNLABELLED: Continence problems during treatment with orlistat (a lipase inhibitor) are caused when susceptible patients are exposed to increased volumes of loose, fatty stool. AIM: To investigate the dose-response effects of loperamide on continence and anorectal function in subjects susceptible to continence problems on orlistat. METHOD: Ten obese subjects enterred a randomized controlled, double-blind study of loperamide at placebo, 2, 4, and 6 mg/day in a factorial design. Continence problems during orlistat treatment were self-assessed by patient diary. Anorectal function and continence were assessed by barostat, manometry, and retention testing. RESULTS: Loperamide increased stool consistency with dose (p = 0.07) and this effect reduced continence problems during orlistat treatment (p < 0.05). A bell-shaped dose-response relationship was present with anal sphincter function (p < 0.01) and anorectal sensitivity (p < 0.01). CONCLUSION: Loperamide has beneficial effects on stool consistency and continence in obese subjects taking orlistat. The effect on stool consistency appeared more important than effects on anorectal function.

Adult↗
PubMed2005

Tegaserod is safe, well tolerated and effective in the treatment of patients with non-diarrhoea irritable bowel syndrome.

OBJECTIVE: To evaluate the safety/tolerability and efficacy of tegaserod, a 5-HT4 receptor partial agonist, in the treatment of patients with non-diarrhoea irritable bowel syndrome (non-D-IBS) in Switzerland. METHODS: This was an 8-week, open-label, prospective, multicentre study. Patients (> or =18 years old) met the Rome II diagnostic criteria for IBS, excluding those with diarrhoea for > or =14 days in the previous 3 months. Details of IBS symptoms experienced in the preceding week were recorded at visit 1 (day 1). Eligible patients received 6 mg tegaserod twice daily for 8 weeks. Adverse events (AEs) and serious AEs were recorded, along with detailed assessment of diarrhoeal episodes. Efficacy assessments included the overall number and percentage of responders after 8 weeks' treatment. RESULTS: A total of 850 patients (72% women; mean age, 51.4 years) were enrolled, and 843 received at least one dose of tegaserod. AEs were reported in 38% of patients, of which 13% were drug-related. Diarrhoea occurred early during treatment (13% in the first week, 7% thereafter), was mild to moderate in severity, was transient and was resolved with continued treatment. In total, 208 patients left the study early, primarily due to AEs. Diarrhoea accounted for 68 of these discontinuations. Nine serious AEs were reported but these were not related to tegaserod treatment. Sixty-six percent of patients responded to tegaserod on the Subject's Global Assessment of relief after 8 weeks. Benefits were also seen across individual IBS symptoms. CONCLUSION: Tegaserod (6 mg twice daily) appears to be safe, well-tolerated and effective in the treatment of non-D-IBS over 8 weeks.

Adolescent↗
PubMed2004

Gastric flow and mixing studied using computer simulation.

The fed human stomach displays regular peristaltic contraction waves that originate in the proximal antrum and propagate to the pylorus. High-resolution concurrent manometry and magnetic resonance imaging (MRI) studies of the stomach suggest a primary function of antral contraction wave (ACW) activity unrelated to gastric emptying. Detailed evaluation is difficult, however, in vivo. Here we analyse the role of ACW activity on intragastric fluid motions, pressure, and mixing with computer simulation. A two-dimensional computer model of the stomach was developed with the 'lattice-Boltzmann' numerical method from the laws of physics, and stomach geometry modelled from MRI. Time changes in gastric volume were specified to match global physiological rates of nutrient liquid emptying. The simulations predicted two basic fluid motions: retrograde 'jets' through ACWs, and circulatory flow between ACWs, both of which contribute to mixing. A well-defined 'zone of mixing', confined to the antrum, was created by the ACWs, with mixing motions enhanced by multiple and narrower ACWs. The simulations also predicted contraction-induced peristaltic pressure waves in the distal antrum consistent with manometric measurements, but with a much lower pressure amplitude than manometric data, indicating that manometric pressure amplitudes reflect direct contact of the catheter with the gastric wall. We conclude that the ACWs are central to gastric mixing, and may also play an indirect role in gastric emptying through local alterations in common cavity pressure.

Computer Simulation↗
PubMed2004

Health care resource utilization and costs of NSAID-induced gastrointestinal toxicity. A population-based study in Switzerland.

BACKGROUND AND AIMS: The well-recognized gastrointestinal toxicity of NSAIDs ranges from mild symptoms to severe complications requiring medical attention and leading to work loss. The present study evaluates the economic burden derived from health care resource utilization and work loss caused by NSAID-induced gastrointestinal toxicity in the Swiss population. The costs induced by conventional and COX2-selective NSAIDs were calculated separately, and the results were then extrapolated for the United States. METHODS: A computer-generated random sampling of the Swiss population (n = 6,118) was administered a questionnaire by phone. Questions investigated NSAID intake, occurrence of adverse effects, consumption of gastroprotective drugs, health care resource utilization and work loss. Country-specific direct and indirect costs associated with NSAID-induced gastrointestinal toxicity were calculated according to current reimbursement costs in Switzerland and the United States. Medication expenses were used to compute separate iatrogenic cost factors for conventional and COX2-selective NSAIDs. The ability of demographic variables and symptoms to predict resource utilization was analyzed by univariate and multivariate analyses. RESULTS: From among the 6,085 responders (99.5% response rate), 294 subjects had gastrointestinal adverse effects associated with NSAID intake. The annual amount spent on NSAID-related adverse effects was CHF 432.2 million for Switzerland and USD 7,425.7 million for the United States. This amount corresponded to CHF 581 and USD 272 per NSAID user, and was primarily due to costs derived from work loss. For Switzerland, 91.1% of total costs were associated with the use of conventional NSAIDs and could be saved by using COX2-NSAIDs instead. While additional 13% of the medication purchase costs are spent for gastrointestinal adverse effects among COX2-selective NSAID users, additional 315% are spent for the same reason among conventional NSAID users. Thus, given similar efficacy and purchase costs in the two drug groups, COX2-selective NSAIDs are 25.1 times more cost-effective than conventional NSAIDs. Language region, place of residence, nationality, marital status, epigastric pain, diarrhea, hematemesis and melena predicted resource utilization. CONCLUSIONS: Costs arising from NSAID-induced gastrointestinal toxicity are considerable and primarily associated with conventional NSAIDs. COX2-selective NSAIDs could decrease this economic burden.

Absenteeism↗
PubMed2004

The physical properties of rectal contents have effects on anorectal continence: insights from a study into the cause of fecal spotting on orlistat.

PURPOSE: The intermittent loss of oil or stool ("spotting") is an adverse effect that occurs in patients taking orlistat; the pathophysiology is unknown. This study was designed to investigate the local effects of orlistat, free fatty acids, and the effects of the physical properties of rectal contents on anorectal function and continence. METHODS: Anorectal physiology and continence function were assessed in ten healthy patients after the application of four test enemas: 1) high-viscosity stool substitute, 2) stool substitute with free fatty acid, 3) low-viscosity oil with placebo, 4) oil with orlistat. Rectal function and capacity were assessed by barostat techniques. Anal resting pressure, squeeze pressure, and squeeze duration were assessed by manometry. A retention test was performed using the same enemas as a quantitative assessment of continence. RESULTS: Orlistat and free fatty acid had no adverse effects on anorectal function or continence. For each enema, the maximum volume retained correlated with rectal capacity (r = 0.85; P < 0.01). Continence during rectal filling was better maintained for high-viscosity stool substitute than low-viscosity oil enemas (P < 0.03). Patients able to maintain effective squeeze pressure retained more of the low-viscosity enemas than those with short squeeze duration (P < 0.01); in contrast, the volume retained of high-viscosity enemas was unaffected by anal sphincter function. CONCLUSIONS: The physical properties of rectal contents, rectal capacity, and voluntary anal sphincter function have effects on continence function in healthy patients. The occurrence of spotting may depend on both intrinsic anorectal function and the effects of orlistat on the volume and physical properties of stool.

Administration, Oral↗
PubMed2004

Patient-controlled analgesia and sedation in gastrointestinal endoscopy.

Variations in pain threshold, drug tolerance, and visceral sensitivity among patients make it difficult to anticipate the appropriate dose of sedation for gastrointestinal endoscopy. Propofol was recently introduced for sedation in endoscopy and has a rapid onset and offset of action, making it an ideal substance for patient-controlled administration. Several controlled trials have demonstrated that during colonoscopy, patient-controlled application of propofol alone or in combination with various opioids is effective,safe, and yields high patient satisfaction. Target-controlled infusion of propofol has shown encouraging results for prolonged upper endoscopy procedures like endoscopic retrograde cholangio pancreatography.

Analgesia, Patient-Controlled↗
PubMed2004

The human organic anion transporting polypeptide 8 (SLCO1B3) gene is transcriptionally repressed by hepatocyte nuclear factor 3beta in hepatocellular carcinoma.

BACKGROUND/AIMS: The organic anion transporting polypeptides (OATPs) mediate the uptake of numerous amphipathic compounds into hepatocytes. Our aim was to study the expression and regulation of OATP8 (OATP1B3, SLC21A8/SLCO1B3) and OATP-C (OATP1B1, SLC21A6/SLCO1B1) in hepatocellular carcinomas (HCC). METHODS: RNA and protein levels in 13 paired HCC and adjacent non-tumor liver samples were quantified by real-time polymerase chain reaction or Western blot, respectively. The OATP8 and OATP-C gene promoters were characterized by luciferase reporter assays and electrophoretic mobility shift assays (EMSA). RESULTS: The expression of OATP8 was decreased in 60% of HCC compared to surrounding non-tumor liver tissue, on both the mRNA and protein levels. Expression of the liver-enriched transcription factor hepatocyte nuclear factor 3beta (HNF3beta) was increased in 70% of HCC and correlated inversely with OATP8 mRNA (r=-0.75, P<0.05) and protein. In contrast to OATP8, expression of OATP-C was not significantly decreased in HCC. In transfected Huh7 cells, OATP8 promoter activity was inhibited by 70% when HNF3beta was cotransfected. An HNF3beta binding site was located at nt -39/-23 by EMSA. The OATP-C promoter was not inhibited by HNF3beta. CONCLUSIONS: HNF3beta represses transcription of the OATP8 but not the OATP-C gene, providing a mechanism for reduced expression of OATP8 in HCC.

Aged↗
PubMed2004

Therapeutic drug monitoring of thiopurine drugs in patients with inflammatory bowel disease or autoimmune hepatitis.

OBJECTIVE: Thiopurine drugs are commonly used immunosuppressants in the treatment of inflammatory bowel disease (IBD) as well as in autoimmune hepatitis (AIH), rheumatic diseases and in transplantation medicine. The relatively narrow therapeutic range requires useful therapy control. Therefore, the purpose of this study was to further investigate the rationale and usefulness of therapeutic drug monitoring in the surveillance of thiopurine drug therapy in Crohn's disease, ulcerative colitis and autoimmune hepatitis. METHODS: 6-Thioguanine nucleotide (TGN) and 6-methylmercaptopurine nucleotide (MMPN) levels were measured in 182 IBD patients and 18 AIH patients using HPLC-UV. RESULTS: In our cohort of IBD patients, 18% had TGN levels < 235 pmol/8 x 10 red blood cells (RBC) (recommended range, 235-450 pmol/8 x 10 RBC), 41% of these patients were sent for drug failure. Twenty-four per cent of the IBD patients had TGN levels > 450 pmol/8 x 10 RBC, but only 27% of these experienced adverse effects. Fifty-nine per cent of the patients having drug failure had TGN levels in the recommended range and could therefore be classified as non-responders. In the AIH cohort 33% of the patients had TGN levels below the recommended range but showed clinical response to therapy. MMPN levels increased with the duration of treatment and could be useful for controlling compliance. There was 8.8% of IBD patients who were heterozygous for non-functional TPMT alleles. CONCLUSIONS: TGN monitoring did not identify significant differences between patient groups but allowed the identification of non-responders from non-compliant patients and allowed the differentiation of mild side effects, such as malaise, from genuine toxicity caused by highly increased TGN levels.

Adolescent↗
PubMed2004

Significance of incidental 18F-FDG accumulations in the gastrointestinal tract in PET/CT: correlation with endoscopic and histopathologic results.

UNLABELLED: This study was undertaken to identify the clinical value of incidentally detected lesions (IDLs) in the gastrointestinal tract (GIT) with (18)F-FDG PET/CT. METHODS: The reported database of 3,281 patients who underwent partial-body (18)F-FDG PET/CT scans from April 2001 to September 2003 was reviewed. Patients with incidental (18)F-FDG accumulations in the GIT that were associated with concomitant abnormal soft-tissue density or wall thickening on the native CT were evaluated. Incidental PET/CT findings were correlated with endoscopic and histopathologic results. RESULTS: According to our selection criteria, 98 (3%) of the 3,281 patients had an IDL of the GIT on (18)F-FDG PET/CT. Correlative endoscopic findings were available in 69 (70%) of 98 patients. Of these, 13 patients (19%) were harboring newly occurring cancers of the GIT in addition to preexisting aerodigestive tract tumors (n = 12) and malignant melanoma (n = 1). Twenty-nine (42%) patients were identified with precancerous lesions, such as advanced colonic adenomas (n = 27), Barrett's esophagus (n = 1), and intestinal metaplasia of the gastric mucosa (n = 1). Inflammatory and other benign GIT lesions were detected in 12 (17%) and 6 (8%) patients, respectively. In 9 (13%) patients, PET/CT was false-positive, showing normal findings in subsequent endoscopic examinations. In 20 (28%) of 69 patients, PET/CT findings had a relevant impact on the clinical management. Twenty-nine (30%) of the 98 patients were not subject to a further endoscopic examination because of the extent and nature of the primary tumor (n = 17), loss to follow-up (n = 7), death shortly after PET (n = 3), and patient unwillingness (n = 2). CONCLUSION: Although IDLs of the GIT on (18)F-FDG PET/CT scans are found only in about 3% of cases, they are associated with a substantial risk of an underlying cancerous or precancerous lesion. Early identification of these occult lesions may have a major impact on the patients' management and outcome.

Aged↗
PubMed2003

Role of liver-enriched transcription factors and nuclear receptors in regulating the human, mouse, and rat NTCP gene.

Hepatic uptake of bile acids is mediated by the Na(+)-taurocholate cotransporting polypeptide (NTCP; SLC10A1) of the basolateral hepatocyte membrane. Several cis-acting elements in the rat Ntcp gene promoter have been characterized. However, little is known about the mechanisms that control the expression of the human or mouse NTCP/Ntcp. We, therefore, compared the transcriptional regulation of the human and mouse NTCP/Ntcp gene with that of the rat. By computer alignment, a sequence in the 5'-regulatory region that is conserved between species was identified near the transcription start site. Huh7 cells were transfected with luciferase constructs containing the conserved region from each species. The hepatocyte nuclear factors (HNF)1alpha and -4alpha and the retinoid X receptor/retinoic acid receptor dimer (RXRalpha/RARalpha) bound and transactivated the rat but not the human or mouse NTCP/Ntcp promoters. In contrast, activation by the CCAAT/enhancer binding protein-beta was specific for human and mouse NTCP/Ntcp. The only consensus motif present in all three species was HNF3beta. HNF3beta formed a specific DNA-protein complex in electrophoretic mobility shift assays and inhibited NTCP/Ntcp promoter activity in cotransfection assays. Finally, a minor repressive effect of bile acids was only found for rat Ntcp. The transcriptional repressor small heterodimer partner (SHP) did not affect NTCP/Ntcp promoter activity. We conclude that 1) the transcriptional regulation of the conserved NTCP/Ntcp 5'-regulatory region differs considerably among human, mouse, and rat; and 2) the conserved NTCP/Ntcp regulatory region is not directly regulated by SHP. Bile acids may regulate NTCP/Ntcp indirectly by modulating the capacity of nuclear factors to activate gene expression.

Animals↗