Biomedical subjects

Li Wang

Publications and source records attributed to Li Wang.

At least 451 records · Page 25Linked to original sources

PubMed2002

[Advanced glycation end products inhibit production of nitric oxide by human endothelial cells through activation of the p38 signal pathway].

OBJECTIVE: To study the effect of advanced glycation end products (AGE) modified protein on nitric oxide (NO) production by human endothelial cells and the possible role of signal transduction pathway in this pathological procedure. METHODS: Human umbilical vein endothelial cells (HUVECs) and HUVEC-derived cell line (ECV304) were cultured in vitro with AGE modified human serum albumin (AGE-HSA) or AGE modified bovine serum albumin (AGE-BSA) of the concentrations of 12.5, 25, and 50 micro g/ml for 2, 4, 8, 12, and 24 hours. NO levels in the supernatant at each time point were determined by using Griess reagents. HUVECs and ECV304 cells incubated with HAS or BSA of the same concentrations were used as controls. The phosphorylation activity of cellular p38 mitogen-activated protein kinase (p38-MAPK) was analyzed by Western blot using a phospho-specific antibody after the cells were incubated with AGE-HAS or AGE-BSA of the concentration of 12.5, 25, 50, and 100 micro g/ml for 5, 15, 30, 60, and 120 minutes. HUVECs were incubated with SB 203580, a specific inhibitor of p38, of the concentrations of 0.075, 0.15, and 0.3 micro mol/L for 4 hours, then the culture with SB 203580 was extracted. The endothelial cells were cleansed with RPMI 1640 culture and then were incubated with AGE-HAS or AGE-BSA for 8 hours. The No level in this supernatant was examined after the above-mentioned method. RESULTS: The NO level in the supernatant of culture of HUVECs incubated with AGE-HAS or AGE-HAS for 2 hours were 92.2% +/- 10.1% and 94.1% +/- 12.5% of the controls respectively. The NO levels reached the lowest values, 72.4% +/- 7.14% and 68.3% +/- 10.9% of the values of the controls respectively after 8-hour incubation with AGE-HAS or AGE-HAS. AGE-HSA and AGE-BSA decreased the NO levels in the supernatant in a dose and time-dependant manner. The unmodified HSA and BSA did not influence the NO production by HUVECs or ECV304 cells. There was no difference in inhibition effect on NO production between AGE-HSA and AGE-BSA (P > 0.05). There was no difference in response to AGE-HSA and AGE-BSA between HUVECs and ECV304 cells (P > 0.05). In the culture of HUVECs or of ECV304 cells incubated with AGE-HSA or AGE-BSA, the p38 phosphorylation activity was obviously enhanced 10 minutes after dose-dependently, reached its peak 30 minutes after, and returned to its basic level in 120 minutes. SB203580 of the concentration of 0.3 micro mol/L completely abolished the inhibitive effect of AGE-albumin on NO production by endothelial cells. CONCLUSION: AGE modified protein inhibits the production of NO by human endothelial cells through activation of the p38 signal pathway. This AGE modification-induced pathobiological cascade may be involved in the pathogenesis of atherosclerosis seen in AGE-associated diseases.

Cells, Cultured↗

PubMed2002

Recombinant arginine deiminase as a potential anti-angiogenic agent.

Arginine deiminase (ADI), isolated from Mycoplasma cell extracts, has been suggested to inhibit endothelial cell growth in vitro. However, anti-angiogenic activity by ADI has not yet been demonstrated. In this study, we investigated the in vitro effect of recombinant ADI (rADI) on the growth, migration, and tube formation of human umbilical vein endothelial (HUVE) cells. Mycoplasma arginine deiminase was cloned by PCR and the rADI was expressed in Escherichia coli. and purified to near homogeneity. The purified recombinant protein was found to have characteristics similar to those of the native enzyme: molecular weight (48 kDa) and specific enzymatic activity of converting L-arginine into citrulline (32.7 U/mg). This recombinant enzyme also exhibited an inhibitory effect on the growth of HUVE cells. The anti-angiogenic activity was demonstrated by in vitro inhibition of migration into the scratch wounded area in HUVE cell monolayers and the inhibition of microvessel tube-like formation of HUVE cells on Matrigel-coated surfaces. These results suggest that arginine deiminase is a potential inhibitor for angiogenesis, and that arginine concentrations may play an important role in regulating neovascularization.

Angiogenesis Inhibitors↗

PubMed2002

Ultrastructure of electrical synapses between nociceptive and anterior pagoda neurons in the CNS of the leech (Whitmania pigra).

We have used electron microscopy to measure quantitatively the morphology of electrical synapses in a circuit that has been proposed to account for the positional discrimination of the leech. Injection of a presynaptic nociceptive sensory neuron and the postsynaptic anterior pagoda neuron with HRP showed gap junctions in the neuropil. After double labeling, La(3+)-treated ganglia revealed labeled gap junctions from 2.0 to 3.5 nm wide. Between the labeled axon terminals, there were innexons with diameters of 8 to 10 nm. The innexon's central pore diameter was 2 nm, and the mean of the center-to-center distance between two innexons was 30 nm. Except for the gap junction areas of nociceptive sensory neuron axon terminals, the other ultrastructural parameters measured by freeze fracture were similar to those of samples labeled with HRP and filled with La(3+). These data suggested that the gap width, innexon diameter, and its central pore do not on their own account for the mechanism of positional discrimination, which may depend rather on the differences in distribution and number of gap junctions.

Animals↗

PubMed2002

Remodeling of organelle-bound actin is required for yeast vacuole fusion.

Actin participates in several intracellular trafficking pathways. We now find that actin, bound to the surface of purified yeast vacuoles in the absence of cytosol or cytoskeleton, regulates the last compartment mixing stage of homotypic vacuole fusion. The Cdc42p GTPase is known to be required for vacuole fusion. We now show that proteins of the Cdc42p-regulated actin remodeling cascade (Cdc42p --> Cla4p --> Las17p/Vrp1p --> Arp2/3 complex --> actin) are enriched on isolated vacuoles. Vacuole fusion is dramatically altered by perturbation of the vacuole-bound actin, either by mutation of the ACT1 gene, addition of specific actin ligands such as latrunculin B or jasplakinolide, antibody to the actin regulatory proteins Las17p (yeast Wiskott-Aldrich syndrome protein) or Arp2/3, or deletion of actin regulatory genes. On docked vacuoles, actin is enriched at the "vertex ring" membrane microdomain where fusion occurs and is required for the terminal steps leading to membrane fusion. This role for actin may extend to other trafficking systems.

Actins↗

PubMed2002

[Association between pre-excitation syndrome and 7q3 D7S505 pseudonym gene].

OBJECTIVE: Pre-excitation syndrome is considered to be autosomal dominant hereditary disease. The objective of this study was to search the genetic foundation of the pre-excitation syndrome. METHODS: Genomic DNA was isolated from peripheral lymphocytes obtained from 44 cases of patients with pre-excitation syndrome and 53 normal persons. Polymorphic short tandem repeats(STR) were amplified using polymerase chain reaction (PCR) and analyzed by polyacrylamide gel electrophoresis. The genotype of each individual was determined by polymorphic STR including D7S505,D7S688,D7S483. Association analysis between the pre-excitation syndrome and the 3 STR (D7S505,D7S483 and D7S688) was tested by genotyping. RESULTS: The relative risk(RR) of alleles A2 A3 A4 and A6 of D7S505 were 1.051 6, 3.432,1.563 1 and 1.714 3 respectively all of which were more than 1, but only the RR of A3 had statistic significant difference, P < 0.05 after tested by kappa(2). It supposed that the distribution of allele A3(266 bp) of D7S505 in patients with pre-excitation syndrome was much higher than that in normal controls, which suggested that pre-excitation syndrome is associated with D7S505. Whereas, there were no significant difference in every allele of D7S483 between the pre-excitation syndrome and normal persons, which suggested that pre-excitation syndrome is not associated with D7S483. CONCLUSION: The pre-excitation syndrome is associated with D7S505,the result is the foundation of the molecular genetics of the disease.

Adolescent↗

PubMed2002

Variant-type PML-RAR(alpha) fusion transcript in acute promyelocytic leukemia: use of a cryptic coding sequence from intron 2 of the RAR(alpha) gene and identification of a new clinical subtype resistant to retinoic acid therapy.

The physiologic actions of retinoic acids (RAs) are mediated through RA receptors (RARs) and retinoid X receptors (RXRs). The RAR(alpha) gene has drawn particular attention because it is the common target in all chromosomal translocations in acute promyelocytic leukemia (APL), a unique model in cancer research that responds to the effect of RA. In the great majority of patients with APL, RAR(alpha) is fused to the PML gene as a result of the t(15;17) translocation. Three distinct types of PML-RAR(alpha) transcripts, long (L), short (S), and variant (V), were identified. The V-type is characterized by truncation of exon 6 of PML and in some cases by the insertion of a variable "spacer" sequence between the truncated PML and RAR(alpha) mRNA fusion partners, although the precise mechanisms underlying formation of the V-type transcript remain unclear. To get further insights into the molecular basis of the t(15;17), we sequenced the entire genomic DNA region of RAR(alpha). Of note, all previously reported "spacer" sequences in V-type transcripts were found in intron 2 of the RAR(alpha) gene and most of these sequences were flanked by gt splice donor sites. In most cases, these "cryptic" coding sequences maintained the ORF of the chimeric transcript. Interestingly, two cases with a relatively long spacer sequence showed APL cellular and clinical resistance to RA treatment. In these cases, the aberrant V-type PML-RAR(alpha) protein displayed increased affinity to the nuclear corepressor protein SMRT, providing further evidence that RA exerts the therapeutic effect on APL through modulation of the RAR-corepressor interaction. Finally, among patients with the L- or S-type PML-RAR(alpha) fusion transcript, some consensus motifs were identified at the hotspots of the chromosome 17q breakpoints within intron 2 of RAR(alpha), strengthening the importance of this intron in the molecular pathogenesis of APL.

Antineoplastic Agents↗

PubMed2002

[Regional intra-arterial infusion chemotherapy for pancreatic cancer: an experimental study].

OBJECTIVE: To verify the feasibility of regional intra-arterial infusion chemotherapy with gemcitabine for the treatment of locally advanced pancreatic cancer. METHODS: 10 Beagle dogs were divided into two groups: the experimental group and the control group. In the experimental group, gemcitabine (45 mg/kg) were infused via a transfemorally placed catheter into the celiac axis and superior mesenteric artery. IAC was given over 30 min with the help of DSA. In the control group, chemotherapy was performed via peripheral veins with the same dosage as the experimental group. Blood samples, heart, lung, liver, kidney, pancreas and parapancreatic tissues were obtained for drug concentration determination and pathological examination. RESULTS: The serum concentration of experimental group were significantly higher than those of the control group 2 hr, 4 hr and 8 hr after treatment (P < 0.05). Area under curve after dosage-based calibration in experimental group was much higher than that in control group (P < 0.05). The mean retention time of the drug in the animal body was significantly longer in experimental group than in control group. Pancreatic gemcitabine titer in experimental group was significantly higher than that in control group 4 hr and 8 hr after drug administration. There were a large number of red blood cells in the renal glomerulus and tubules, congestion and hemorrahge in the pulmonary capillaries and myocardium in the control group according to pathological examinations. However, infiltration of neutrophilic white blood cells, hemorrahge and fibrinous exudation were present in parapancreatic tissues which were absent in the group. CONCLUSION: Regional intra-arterial infusion chemotherapy with gemcitabine could increase serum and pancreatic drug concentration, prolongs retention time of the drug in the animal body, and is feasible in the treatment of pancreatic cancer.

Animals↗

PubMed2002

Role of skeletal muscle Na+-K+ ATPase activity in increased lactate production in sub-acute sepsis.

Bacterial sepsis is frequently accompanied by increased blood concentration of lactic acid, which traditionally is attributed to poor tissue perfusion, hypoxia and anaerobic glycolysis. Therapy aimed at improving oxygen delivery to tissues often does not correct the hyperlactatemia, suggesting that high blood lactate in sepsis is not due to hypoxia. Various tissues, including skeletal muscle, demonstrate increased lactate production under well-oxygenated conditions when the activity of the Na+-K+ ATPase is stimulated. Although both muscle Na+-K+ ATPase activity and muscle plasma membrane content of Na+, K+-ATPase subunits are increased in sepsis, no studies in vivo have demonstrated correlation between lactate production and changes in intracellular Na+ and K+ resulting from increased Na+-K+ pump activity in sepsis. Plasma concentrations of lactate and epinephrine, a known stimulator of the Na+-K+ pump, were increased in rats made septic by E. coli injection. Muscle lactate content was significantly increased in septic rats, although muscle ATP and phosphocreatine remained normal, suggesting oxygen delivery remained adequate for mitochondrial energy metabolism. In septic rats, muscle intracellular ratio of Na+:K+ was significantly reduced, indicating increased Na+-K+ pump activity. These data thus demonstrate that increased muscle lactate during sepsis correlates with evidence of elevated muscle Na+-K+ ATPase activity, but not with evidence of impaired oxidative metabolism. This study also further supports a role for epinephrine in this process.

Adenosine Triphosphate↗

PubMed2002

Vacuole fusion at a ring of vertex docking sites leaves membrane fragments within the organelle.

Three membrane microdomains can be identified on docked vacuoles: "outside" membrane, not in contact with other vacuoles, "boundary" membrane that contacts adjacent vacuoles, and "vertices," where boundary and outside membrane meet. In living cells and in vitro, vacuole fusion occurs at vertices rather than from a central pore expanding radially. Vertex fusion leaves boundary membrane within the fused organelle and is an unexpected pathway for the formation of intralumenal membranes. Proteins that regulate docking and fusion (Vac8p, the GTPase Ypt7p, its HOPS/Vps-C effector complex, the t-SNARE Vam3p, and protein phosphatase 1) accumulate at these vertices during docking. Their vertex enrichment requires cis-SNARE complex disassembly and is thus part of the normal fusion pathway.

Biological Transport↗

PubMed2002

Extreme mtDNA homogeneity in continental Asian populations.

Mitochondrial DNA (mtDNA) variation in continental Asia has not been well-studied. Here, we report mtDNA HV1 sequences for 84 Xi'an and 82 Changsha Han Chinese, 89 Honshu Japanese, and 35 Vietnamese. Comparison of these sequences with other Asian mtDNA sequences reveals high variability within populations, but extremely low differentiation among Asian populations. Correlations between genetic distance and geographic distance, based on mtDNA and Y chromosome variation, indicate a higher migration rate in females than in males. This may reflect patrilocality, as suggested previously, but another plausible hypothesis is that the demographic expansion associated with the spread of agriculture in Asia may be responsible for the extreme genetic homogeneity in Asia.

Asia↗

PubMed2002

Nerve growth factor and enhancement of proliferation, invasion, and tumorigenicity of pancreatic cancer cells.

Nerve growth factor (NGF) exerts both stimulatory and inhibitory effects on neuronal and certain non-neuronal tumors. In pancreatic cancer NGF is overexpressed, and this overexpression is associated with increased perineural invasion. NGF has the potential to stimulate the growth of some pancreatic cancer cell lines, and this effect is mediated by the phosphorylation of tyrosine kinase receptor A and mitogen-activated protein kinase activation; it is dependent on the expression levels of tyrosine kinase receptor A and p75 receptors. To determine whether cancer cell-derived NGF can participate in the regulation of pancreatic cancer cell proliferation, PANC-1 human pancreatic cancer cells were stably transfected with a full-length human beta-NGF expression vector. In vitro and in vivo growth characteristics were analyzed by proliferation assays and invasion assays and in a nude mouse tumor model. Stable transfection of NGF in PANC-1 cells resulted in enhanced anchorage-dependent growth, with a decrease in doubling times of up to 50%, and in an approximately twofold increase in anchorage-independent cell growth and cell invasion. Furthermore, stably transfected PANC-1 cells showed enhanced tumorigenicity in nude mice. These results suggest that NGF has the capacity to act in a paracrine and/or an autocrine manner in pancreatic cancer and that it enhances cancer cell growth and invasion in vivo, thereby contributing to the aggressiveness and poor prognosis of this disease.

Animals↗

PubMed2002

Glypican-3 expression is markedly decreased in human gastric cancer but not in esophageal cancer.

BACKGROUND: Deregulation of the expression of glypican-3, a heparan sulfate proteoglycan, has been demonstrated in several human cancers. METHODS: In the present study, glypican-3 mRNA expression was analyzed by Northern blotting and in situ hybridization in 20 normal and 41 cancerous esophageal specimens as well as in 15 normal and 32 cancerous gastric tissues. RESULTS: Glypican-3 mRNA was expressed in both normal and esophageal cancer tissues without a significant difference between normal and cancerous tissues, and without a correlation with histological type, tumor stage, tumor grade, or patient survival. Moderate to strong glypican-3 mRNA signals were found in the cytoplasm of squamous epithelial cells of the normal esophagus. In both squamous and adenocarcinomas of the esophagus glypican-3 mRNA signals were also moderately to strongly present in the cytoplasm of the cancer cells. In gastric tissues, glypican-3 mRNA was present in 53% of normal gastric tissue samples, but was below the detection level in all examined gastric cancer samples. Glypican-3 mRNA signals were moderately to strongly present in the cytoplasm of gastric mucosal epithelial cells, but were only very faintly present in some cancer cells. CONCLUSIONS: Glypican-3 may be involved in the growth control of normal esophageal and gastric epithelial cells. Furthermore, our results suggest that glypican-3 may play a tumor suppressor role in gastric but not in esophageal cancer.

Adult↗

PubMed2002

A comparative analysis of five methods of determining corneal refractive power in eyes that have undergone myopic laser in situ keratomileusis.

OBJECTIVE: To evaluate the accuracy of computerized videokeratography, keratometry, and the Gaussian optics formula for measuring corneal refractive power in patients after myopic laser in situ keratomileusis (LASIK). DESIGN: Noncomparative case series. PARTICIPANTS: One hundred eyes of 63 patients (mean age, 45.0 +/- 10.9 [standard deviation] years) who underwent LASIK were included in the study. METHODS: Using the clinical history method as the standard, we evaluated the accuracy of values of corneal refractive power derived from computerized videokeratography (the EffRP value of the EyeSys Corneal Analysis System, which averages corneal refractive power over the central 3 mm), keratometry (K), the Gaussian optics formula (GauRP), and values of EffRP and keratometry as modified according to the amount of LASIK-induced refractive change. MAIN OUTCOME MEASURES: Correlation of measured corneal power values to those obtained using clinical history method (HisRP). RESULTS: Although the values for HisRP were significantly correlated with postoperative EffRP and K values and with GauRP, postoperative EffRP and K values were higher than HisRP (0.87 +/- 0.68 diopters [D] and 1.16 +/- 1.10 D, respectively), and GauRP were lower than HisRP (0.44 +/- 0.66 D) (P < 0.001 for all three comparisons). The differences between HisRP and both postoperative EffRP and K values increased significantly with the amount of myopic correction. The most accurate results were obtained by modifying the postoperative values of EffRP according to the amount of LASIK-induced refractive change; 70% of these values were within +/- 0.5 D and 94% within +/- 1 D of HisRP values. CONCLUSIONS: Using the clinical history method as the standard, we found that the most accurate method for determining corneal refractive power in post-LASIK eyes was to adjust the postoperative corneal measurement according to the amount of LASIK-induced refractive change.

Adult↗

PubMed2002

The effects of antiepileptic drugs on spatial learning and hippocampal protein kinase C gamma in immature rats.

This study was conducted to determine if alterations in hippocampal protein kinase C (PKC) gamma is one of the cellular mechanisms by which conventional antiepileptic drugs affect learning and memory. Wistar Rats (21-day-old) were divided into five groups: (1) control (no training and drugs); (2) training group (no drugs); (3) phenobarbital (PB) group; (4) carbamazepine (CBZ) group; and (5) valproate (VPA) group. A hippocampus dependent learning task (spatial changing learning) was used in the latter four groups lasting a total of 10 days. Correct responding rate of training group was significantly higher (P < 0.05) than in the PB, CBZ and VPA group. The PKC gamma staining intensity in hippocampal CA1-2 region of training group was significant greater than that of the control and PB group. There was no difference in staining intensities between the CBZ, VPA group or training group. The amount of PKC gamma located in plasma membrane of hippocampal neurons was significantly higher in the training group (P < 0.05) than the control, PB and VPA groups. No differences were found between the training and CBZ group. Lastly, the amount of PKC gamma in cytosol of hippocampus did not significantly differ between any of the five groups. These results indicate that the three antiepileptic drugs used in this study all disturbed the spatial learning of immature rats. Spatial learning was concomitant with activation of PKC gamma in hippocampal neurons. PB and VPA likely adversely affect learning and memory by interfering with PKC gamma activation, whereas CBZ may act by a different mechanism, possibly in the post-translocation process or by a PKC gamma independent pathway.

Animals↗

PubMed2002

Comparison of a ray-tracing refractometer, autorefractor, and computerized videokeratography in measuring pseudophakic eyes.

PURPOSE: To test the accuracy and reliability of the first-generation prototype of Tracey-1, a ray-tracing refractometer. SETTING: Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA. METHODS: The refractive spherical equivalent (SE) and astigmatism measured by Tracey-1, subjective manifest refraction (MR), and autorefraction (AR) (Nidek AR-3300) were compared in 58 pseudophakic eyes of 44 patients with a mean age of 69.95 years +/- 8.6 (SD). The astigmatic values obtained from Tracey-1 and computerized videokeratography were also compared. Astigmatism values were compared using power vector analysis. RESULTS: The mean SEs measured by MR, Tracey, and AR were -0.76 diopter (D) +/- 0.96 (SD) (range 1.00 to -3.00 D), 0.37 +/- 0.64 D (range 1.68 to -1.49 D), and -0.44 +/- 1.13 D (range 1.63 to -3.50 D), respectively. The Pearson correlation coefficients between MR and Tracey values and between MR and AR values were high (r = 0.895 and r = 0.875, respectively; both P < .0001). However, the mean difference between the Tracey and MR values was 1.13 +/- 0.48 D (range 2.45 to -0.06 D) (P < .001). The mean cylindrical differences between MR and Tracey and between MR and AR were 0.03 +/- 0.51 D (range 1.22 to -1.07 D) (P = .709) and -0.30 +/- 0.62 D (range 0.50 to -2.25 D) (P = .003), respectively. Power vector analysis revealed difference vectors of -0.16 x 60 between Tracey and MR and -0.22 x 87 between AR and MR. CONCLUSIONS: Spherical and cylindrical refractive data obtained with the Tracey system correlated well with those derived from MR; however, there was a mean spherical error of approximately 1.10 D. Further work is required to refine the accuracy and range of this device.

Aged↗

PubMed2002

Methods of estimating corneal refractive power after hyperopic laser in situ keratomileusis.

PURPOSE: To evaluate and compare methods of estimating corneal refractive power after hyperopic laser in situ keratomileusis (LASIK). SETTING: Cullen Eye Institute, Baylor College of Medicine, Houston, Texas, USA. METHODS: Using the clinical history method (HisRP) as the standard, the accuracy of values of corneal refractive power derived from the EyeSys Corneal Analysis System or Humphrey Atlas computerized videokeratography, the thin lens formula, and corneal topographic measurements modified according to the amount of LASIK-induced refractive change were evaluated. RESULTS: Thirty-four eyes of 19 patients were evaluated using EyeSys and 27 eyes of 16 patients were examined using Humphrey Atlas. Although the values derived from corneal topography and the thin lens formula correlated well with HisRP, the differences between HisRP and topographic values increased significantly with increasing hyperopic correction. When the values of corneal topographic measurements were modified according to the amount of LASIK-induced refractive change, the accuracy was significantly improved (all P <.05) and the percentages of eyes within 0.5 diopter (D) and 1.0 D of the HisRP values exceeded 71% and 94%, respectively. CONCLUSION: Using the clinical history method as the standard, the most accurate method for determining corneal refractive power in hyperopic LASIK eyes was to adjust the postoperative corneal topographic measurement according to the amount of LASIK-induced refractive change.

Adult↗

PubMed2002

Separation of biosynthetic polyunsaturated fatty acid (PUFA) with supercritical fluid.

The separation of biosynthetic polyunsaturated fatty acid (PUFA) was undertaken with supercritical fluid. The polyunsaturated fatty acid was synthesised by WL-1021, which is a strain of marine bacterium isolated from marine fish. The polyunsaturated fatty acid can be very efficiently extracted from WL-1021 that has the characteristics of rapid growth in the artificial medium. The PUFA in WL-1021 has been successfully separated by supercritical fluid extraction (SFE). The SFE process parameters including pressure, temperature and culture temperature variations have been measured by High Performance Liquid Chromatography (HPLC), GC/FT-IR and GC/MS.

Animals↗

PubMed2002

Redundant pathways for negative feedback regulation of bile acid production.

The orphan nuclear hormone receptor SHP has been proposed to have a key role in the negative feedback regulation of bile acid production. Consistent with this, mice lacking the SHP gene exhibit mild defects in bile acid homeostasis and fail to repress cholesterol 7-alpha-hydroxylase expression in response to a specific agonist for the bile acid receptor FXR. However, this repression is retained in SHP null mice fed bile acids, demonstrating the existence of compensatory repression pathways of bile acid signaling. We provide evidence for two such pathways, based on activation of the xenobiotic receptor PXR or the c-Jun N-terminal kinase JNK. We conclude that redundant mechanisms regulate this critical aspect of cholesterol homeostasis.

Animals↗