Hepatocyte-specific CCAAT/enhancer binding protein α restricts liver fibrosis progression.

Metabolic dysfunction-associated steatohepatitis (MASH) - previously described as nonalcoholic steatohepatitis (NASH) - is a major driver of liver fibrosis in humans, while liver fibrosis is a key determinant of all-cause mortality in liver disease independent of MASH occurrence. CCAAT/enhancer binding protein α (CEBPA), as a versatile ligand-independent transcriptional factor, has an important function in myeloid cells, and is under clinical evaluation for cancer therapy. CEBPA is also expressed in hepatocytes and regulates glucolipid homeostasis; however, the role of hepatocyte-specific CEBPA in modulating liver fibrosis progression is largely unknown. Here, hepatic CEBPA expression was found to be decreased during MASH progression both in humans and mice, and hepatic CEBPA mRNA was negatively correlated with MASH fibrosis in the human liver. CebpaΔHep mice had markedly enhanced liver fibrosis induced by a high-fat, high-cholesterol, high-fructose diet or carbon tetrachloride. Temporal and spatial hepatocyte-specific CEBPA loss at the progressive stage of MASH in CebpaΔHep,ERT2 mice functionally promoted liver fibrosis. Mechanistically, hepatocyte CEBPA directly repressed Spp1 transactivation to reduce the secretion of osteopontin, a fibrogenesis inducer of hepatic stellate cells. Forced hepatocyte-specific CEBPA expression reduced MASH-associated liver fibrosis. These results demonstrate an important role for hepatocyte-specific CEBPA in liver fibrosis progression, and may help guide the therapeutic discoveries targeting hepatocyte CEBPA for the treatment of liver fibrosis.

Direct evidence of substorm-related impulsive injections of electrons at Mercury.

Mercury's magnetosphere is known to involve fundamental processes releasing particles and energy like at Earth due to the solar wind interaction. The resulting cycle is however much faster and involves acceleration, transport, loss, and recycling of plasma. Direct experimental evidence for the roles of electrons during this cycle is however missing. Here we show that in-situ plasma observations obtained during BepiColombo's first Mercury flyby reveal a compressed magnetosphere hosts of quasi-periodic fluctuations, including the original observation of dynamic phenomena in the post-midnight, southern magnetosphere. The energy-time dispersed electron enhancements support the occurrence of substorm-related, multiple, impulsive injections of electrons that ultimately precipitate onto its surface and induce X-ray fluorescence. These observations reveal that electron injections and subsequent energy-dependent drift now observed throughout Solar System is a universal mechanism that generates aurorae despite the differences in structure and dynamics of the planetary magnetospheres.

Forecasting Heliospheric CME Solar-Wind Parameters Using the UCSD Time-Dependent Tomography and ISEE Interplanetary Scintillation Data: The 10 March 2022 CME.

Remotely sensed interplanetary scintillation (IPS) data from the Institute for Space-Earth Environmental Research (ISEE), Japan, allows a determination of solar-wind parameters throughout the inner heliosphere. We show the 3D analysis technique developed for these data sets that forecast plasma velocity, density, and component magnetic fields at Earth, as well at the other inner heliospheric planets and spacecraft. One excellent coronal mass ejection (CME) example that occurred on the 10 March 2022 was viewed not only in the ISEE IPS analyses, but also by the spacecraft near Earth that measured the CME arrival at one AU. Solar Orbiter, that was nearly aligned along the Earth radial at 0.45 AU, also measured the CME in plasma density, velocity, and magnetic field. BepiColombo at 0.42 AU was also aligned with the STEREO A spacecraft, and viewed this CME. The instruments used here from BepiColombo include: 1) the European-Space-Agency Mercury-Planetary-Orbiter magnetic field measurements; 2) the Japan Aerospace Exploration Agency Mio spacecraft Solar Particle Monitor that viewed the CME Forbush decrease, and the Mercury Plasma Experiment/Mercury Electron Analyzer instruments that measured particles and solar-wind density from below the spacecraft protective sunshield covering. This article summarizes the analysis using ISEE, Japan real-time data for these forecasts: it provides a synopsis of the results and confirmation of the CME event morphology after its arrival, and discusses how future IPS analyses can augment these results.

PPARα activation partially drives NAFLD development in liver-specific Hnf4a-null mice.

HNF4α regulates various genes to maintain liver function. There have been reports linking HNF4α expression to the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis. In this study, liver-specific Hnf4a-deficient mice (Hnf4aΔHep mice) developed hepatosteatosis and liver fibrosis, and they were found to have difficulty utilizing glucose. In Hnf4aΔHep mice, the expression of fatty acid oxidation-related genes, which are PPARα target genes, was increased in contrast to the decreased expression of PPARα, suggesting that Hnf4aΔHep mice take up more lipids in the liver instead of glucose. Furthermore, Hnf4aΔHep/Ppara-/- mice, which are simultaneously deficient in HNF4α and PPARα, showed improved hepatosteatosis and fibrosis. Increased C18:1 and C18:1/C18:0 ratio was observed in the livers of Hnf4aΔHep mice, and the transactivation of PPARα target gene was induced by C18:1. When the C18:1/C18:0 ratio was close to that of Hnf4aΔHep mouse liver, a significant increase in transactivation was observed. In addition, the expression of Pgc1a, a coactivator of PPARs, was increased, suggesting that elevated C18:1 and Pgc1a expression could contribute to PPARα activation in Hnf4aΔHep mice. These insights may contribute to the development of new diagnostic and therapeutic approaches for NAFLD by focusing on the HNF4α and PPARα signaling cascade.

MESSENGER Observations of Planetary Ion Enhancements at Mercury's Northern Magnetospheric Cusp During Flux Transfer Event Showers.

At Mercury, several processes can release ions and neutrals out of the planet's surface. Here we present enhancements of planetary ions (Na+-group ions) in Mercury's northern magnetospheric cusp during flux transfer event (FTE) "showers." FTE showers are intervals of intense dayside magnetopause reconnection, during which FTEs are observed in quick succession, that is, only separated by a few seconds. This study identifies 1953 FTE shower intervals and 1795 Non-FTE shower intervals. During the shower intervals, this study shows that the FTEs form a solar wind entry layer equatorward of the northern magnetospheric cusp. In this entry layer, solar wind ions are accelerated and move downward (i.e., planetward) toward the cusp, which sputter upward-moving planetary ions with a particle flux of 1 × 1011 m-2 s-1 within 1 min. The precipitation rate is estimated to increase by an order of magnitude during FTE showers, to 2 × 1025 s-1, and the neutral density of the exosphere could vary by >10% in response to this FTE-driven sputtering. Such rapid large-scale variations driven by dayside reconnection may explain the minute-to-minute changes in Mercury's exosphere, especially on the high latitudes, observed by ground-based telescopes on Earth. Our MESSENGER in situ observation of enhanced planetary ions in the entry layer likely corresponds to an escape channel for Mercury's planetary ions. Comprehensive, future multipoint measurements made by BepiColombo will greatly enhance our understanding of the processes contributing to Mercury's dynamic exosphere and magnetosphere.

KAGUYA observation of global emissions of indigenous carbon ions from the Moon.

Carbon is a volatile element that has a considerable influence on the formation and evolution of planetary bodies, although it was previously believed to be depleted in the Moon. We present observations by the lunar orbiter KAGUYA of carbon ions emitted from the Moon. These emissions were distributed over almost the total lunar surface, but amounts were differed with respect to lunar geographical areas. The estimated emission fluxes to space were ~5.0 × 104 per square centimeter per second, which is greater than possible ongoing supplies from the solar wind and micrometeoroids. Our estimates demonstrate that indigenous carbon exists over the entire Moon, supporting the hypothesis of a carbon-containing Moon, where the carbon was embedded at its formation and/or was transported billions of years ago.

Discovery of BMS-986235/LAR-1219: A Potent Formyl Peptide Receptor 2 (FPR2) Selective Agonist for the Prevention of Heart Failure.

Formyl peptide receptor 2 (FPR2) agonists can stimulate resolution of inflammation and may have utility for treatment of diseases caused by chronic inflammation, including heart failure. We report the discovery of a potent and selective FPR2 agonist and its evaluation in a mouse heart failure model. A simple linear urea with moderate agonist activity served as the starting point for optimization. Introduction of a pyrrolidinone core accessed a rigid conformation that produced potent FPR2 and FPR1 agonists. Optimization of lactam substituents led to the discovery of the FPR2 selective agonist 13c, BMS-986235/LAR-1219. In cellular assays 13c inhibited neutrophil chemotaxis and stimulated macrophage phagocytosis, key end points to promote resolution of inflammation. Cardiac structure and functional improvements were observed in a mouse heart failure model following treatment with BMS-986235/LAR-1219.

Energy partitioning constraints at kinetic scales in low-ß turbulence.

Turbulence is a fundamental physical process through which energy injected into a system at large scales cascades to smaller scales. In collisionless plasmas, turbulence provides a critical mechanism for dissipating electromagnetic energy. Here we present observations of plasma fluctuations in low-ß turbulence using data from NASA's Magnetospheric Multiscale mission in Earth's magnetosheath. We provide constraints on the partitioning of turbulent energy density in the fluid, ion-kinetic, and electron-kinetic ranges. Magnetic field fluctuations dominated the energy density spectrum throughout the fluid and ion-kinetic ranges, consistent with previous observations of turbulence in similar plasma regimes. However, at scales shorter than the electron inertial length, fluctuation power in electron kinetic energy significantly exceeded that of the magnetic field, resulting in an electron-motion-regulated cascade at small scales. This dominance should be highly relevant for the study of turbulence in highly magnetized laboratory and astrophysical plasmas.

Detection of Gut Dysbiosis due to Reduced Clostridium Subcluster XIVa Using the Fecal or Serum Bile Acid Profile.

Background: Dysbiosis, especially a reduced Clostridium subcluster XIVa (XIVa), has been reported in several gastrointestinal diseases. Since XIVa is thought to be the main bacterial cluster that metabolizes bile acids (BAs) in the human intestine, we hypothesized that the BA profile in feces, and possibly in serum, could be a convenient biomarker for intestinal XIVa activity. Methods: First, blood and feces were collected from 26 healthy controls and 20 patients with gastrointestinal diseases, and the relationships among fecal microbiomes and fecal and serum BA compositions were studied. Second, serum BA compositions of 30 healthy controls and the remission and exacerbation states of 14 Crohn's disease (CD) and 12 ulcerative colitis (UC) patients were compared. Fecal microbiomes were analyzed by terminal restriction fragment length polymorphism analysis, and BA compositions were quantified by HPLC-MS/MS. Results: The highest positive correlation was observed between the fecal XIVa proportion and fecal unconjugated deoxycholic acid (DCA)/(DCA+unconjugated cholic acid [CA]) (r = 0.77, P < 0.0001) or serum DCA/(DCA+CA) (r = 0.52, P < 0.001). Diurnal variation in serum XIVa candidate markers also showed that DCA/(DCA+CA) was most stable and not affected by the contraction of the gallbladder. Serum DCA/(DCA+CA) was not significantly different between remission and exacerbation states in either CD or UC patients, but was significantly reduced in those in the remission state of CD and the remission and exacerbation states of UC compared with healthy controls (P < 0.05). Conclusions: Decreased XIVa exhibits a strong correlation with reduced intestinal BA metabolism. Fecal and serum DCA/(DCA+CA) could be useful surrogate markers for the intestinal proportion of XIVa.

Discovery of novel pyrazolo[1,5-a]pyridine-based EP1 receptor antagonists by scaffold hopping: Design, synthesis, and structure-activity relationships.

A scaffold-hopping strategy towards a new pyrazolo[1,5-a]pyridine based core using molecular hybridization of two structurally distinct EP1 antagonists, followed by structure-activity relationship-guided optimization, resulted in the identification of potent EP1 antagonists exemplified by 4c, 4f, and 4j, which were shown to reduce pathological intravesical pressure in rats when administered at 1mg/kg iv.

Wave-particle energy exchange directly observed in a kinetic Alfvén-branch wave.

Alfvén waves are fundamental plasma wave modes that permeate the universe. At small kinetic scales, they provide a critical mechanism for the transfer of energy between electromagnetic fields and charged particles. These waves are important not only in planetary magnetospheres, heliospheres and astrophysical systems but also in laboratory plasma experiments and fusion reactors. Through measurement of charged particles and electromagnetic fields with NASA's Magnetospheric Multiscale (MMS) mission, we utilize Earth's magnetosphere as a plasma physics laboratory. Here we confirm the conservative energy exchange between the electromagnetic field fluctuations and the charged particles that comprise an undamped kinetic Alfvén wave. Electrons confined between adjacent wave peaks may have contributed to saturation of damping effects via nonlinear particle trapping. The investigation of these detailed wave dynamics has been unexplored territory in experimental plasma physics and is only recently enabled by high-resolution MMS observations.

Simultaneous quantification of salivary 3-hydroxybutyrate, 3-hydroxyisobutyrate, 3-hydroxy-3-methylbutyrate, and 2-hydroxybutyrate as possible markers of amino acid and fatty acid catabolic pathways by LC-ESI-MS/MS.

We have developed a highly sensitive and specific method for quantification of salivary 3-hydroxybutyrate (3HB), 3-hydroxyisobutyrate (3HIB), 3-hydroxy-3-methylbutyrate (3HMB) and 2-hydroxybutyrate (2HB), which could be new non-invasive biomarkers for catabolic pathways of fatty acids/ketogenic amino acids, valine, leucine, and methionine/threonine/α-ketobutyrate, respectively. The four hydroxybutyrates (3HB, 3HIB, 3HMB, and 2HB) were extracted from 5 µl of saliva, converted to 2-pyridylmethyl (2PM) ester derivatives, and measured by liquid chromatography-tandem mass spectrometry in positive electrospray ionization mode. [(13)C4]3HB was used as an internal standard. The detection limits for the 2PM esters were <1 pg (7.9-9.6 fmol) on-column (signal-to-noise ratio = 3). Reproducibilities and recoveries of the hydroxybutyrates were validated according to one-way layout and polynomial equation, respectively. The variances between sample preparations and between measurements were calculated to be 0.45-5.28 and 0.54-3.45 %, respectively. Experiments performed using 5 µl of saliva spiked with 3.8-154.4 pmol of the four hydroxybutyrates gave recoveries of 98.5 to 108.8 %, with a mean recovery of 104.1 %. In vitro experiments in hepatocytes or skeletal muscle cells showed that addition of palmitic acid, valine, leucine or α-ketobutyrate to culture medium markedly increased the targeted hydroxybutyrate concentrations. The salivary concentration of each targeted hydroxybutyrate was positively correlated with that in serum, and the salivary levels were elevated in patients with liver cirrhosis, which is characterized by upregulated catabolism of lipids and amino acids. The proposed method is useful for quantification of salivary 3HB, 3HIB, 3HMB, and 2HB for monitoring of catabolic activities of amino acids and fatty acids.

Creation of Customized Bioactivity within a 14-Membered Macrolide Scaffold: Design, Synthesis, and Biological Evaluation Using a Family-18 Chitinase.

Argifin, a 17-membered pentapeptide, inhibits chitinase. As argifin has properties that render it unsuitable as a drug development candidate, we devised a mechanism to create the structural component of argifin that bestows the chitinase inhibition and introduce it into a 14-membered macrolide scaffold. Here we describe (1) the designed macrolide, which exhibits ∼200-fold more potent chitinase inhibition than argifin, (2) the binding modes of the macrolide with Serratia marcescens chitinase B, and (3) the computed analysis explaining the reason for derivatives displaying increased inhibition compared to argifin, the macrolide aglycone displaying inhibition in a nanomolar range. This promises a class of chitinase inhibitors with novel skeletons, providing innovative insight for drug design and the use of macrolides as adaptable, flexible templates for use in drug discovery research and development.

Serum carnitine as an independent biomarker of malnutrition in patients with impaired oral intake.

Carnitine is a vitamin-like compound that plays important roles in fatty acid ß-oxidation and the control of the mitochondrial coenzyme A/acetyl-CoA ratio. However, carnitine is not added to ordinary enteral nutrition or total parenteral nutrition. In this study, we determined the serum carnitine concentrations in subjects receiving ordinary enteral nutrition (EN) or total parenteral nutrition (TPN) and in patients with inflammatory bowel diseases to compare its levels with those of other nutritional markers. Serum samples obtained from 11 EN and 11 TPN patients and 82 healthy controls were examined. In addition, 10 Crohn's disease and 10 ulcerative colitis patients with malnutrition who were barely able to ingest an ordinary diet were also evaluated. Carnitine and its derivatives were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The carnitine concentrations in EN and TPN subjects were significantly lower compared with those of the control subjects. Neither the serum albumin nor the total cholesterol level was correlated with the carnitine concentration, although a significant positive correlation was found between the serum albumin and total cholesterol levels. Indeed, patients with CD and UC showed significantly reduced serum albumin and/or total cholesterol levels, but their carnitine concentrations remained normal. In conclusion, only a complete blockade of an ordinary diet, such as EN or TPN, caused a reduction in the serum carnitine concentration. Serum carnitine may be an independent biomarker of malnutrition, and its supplementation is needed in EN and TPN subjects even if their serum albumin and total cholesterol levels are normal.

Small-bowel mucosal injuries in low-dose aspirin users with obscure gastrointestinal bleeding.

AIM: To investigate the clinical differences between small intestinal injuries in low-dose aspirin (LDA) users and in non-steroidal anti-inflammatory drug (NSAID) users who were examined by capsule endoscopy (CE) for obscure gastrointestinal bleeding (OGIB). METHODS: A total of 181 patients who underwent CE for OGIB were included in this study. Based on clinical records, laboratory data such as hemoglobin levels, major symptoms, underlying diseases, the types and duration of LDA and NSAID use, and endoscopic characteristics of CE were reviewed. RESULTS: Out of a total of 45 cases of erosive lesions, 27 cases were taking LDA or NSAIDs (7 were on NSAIDs, 9 were on LDA alone, 9 were on LDA and thienopyridine, and 2 were on LDA and warfarin).The prevalence of ulcers or erosion during chronic use of LDA, LDA and the anti-platelet drug thienopyridine (clopidogrel or ticlopidine), and NSAIDs were 64.3%, 80.0%, and 75.0%, respectively. Erosive lesions were observed predominantly in chronic LDA users, while ulcerative lesions were detected mainly in NSAID users. However, concomitant use of thienopyridine such as clopidogrel with LDA increased the proportion of ulcers. The erosive lesions were located in the whole of the small intestine (jejunum and ileum), whereas ulcerative lesions were mainly observed in the ileum (P < 0.05). CONCLUSION: Our CE findings indicate that chronic LDA users and NSAID users show different types and locations of small-bowel mucosal injuries. The concomitant use of anti-platelet drugs with LDA tends to exacerbate the injuries from LDA-type to NSAID-type injuries.

Human intestinal spirochaetosis in two ulcerative colitis patients.

A histological examination of colonic biopsies of the longitudinal and irregularly-shaped ulcerative lesions of a 37-year-old man and 61-year-old man with ulcerative colitis showed so-called "fringe formation," a typical finding of Brachyspira infection. The antibody titer to Brachyspira aalborgi showed marked elevation in both cases, and the patients were each treated with 1,000 mg of metronidazole for 14 days. Colonoscopy performed after treatment showed an improvement in the ulcerative lesions in both patients. These results indicate the possibility that intestinal spirochaetosis infection should be considered as an infectious complication in patients with ulcerative colitis receiving long-term steroid therapy.

Post-therapeutic needle biopsy in patients with hepatocellular carcinoma is a useful tool to evaluate response to proton irradiation.

AIM: Proton beam therapy is safe and more effective than conventional radiation therapy for the local control of nodular hepatocellular carcinoma (HCC). However, evaluating therapeutic response by imaging is not accurate during the early post-irradiation period. Therefore, we examined whether the histopathological study of biopsy specimens obtained at 3 weeks after irradiation can be used to more accurately assess therapeutic response. METHODS: Fifteen HCC lesions from 13 patients were treated with proton beam irradiation. Tissue biopsy samples were obtained using abdominal ultrasound-guided percutaneous fine-needle aspiration from the center of the tumor before, 3 weeks after and 1 year post-proton therapy. The specimens were examined after staining with hematoxylin-eosin (HE) and a MIB-1 antibody. RESULTS: MIB-1 labeling indices (LI) before treatment were 13.0 ± 8.5% (mean ± SD; range, 0.6-27.0), whereas those 3 weeks after proton therapy were significantly reduced to 3.2 ± 2.4% (range, 0.6-8.9) (P < 0.05). Although the tumor size was reduced, we did not observe a reduction in tumor blood flow by dynamic computed tomography or degenerative changes by HE. All lesions that displayed reduced MIB-1 LI at 3 weeks post-proton treatment were ultimately diagnosed as complete response at 1 year after treatment. In contrast, one case with increased MIB-1 LI at 3 weeks had significant tumor size progression at 1 year post-treatment. CONCLUSION: The percutaneous fine-needle aspiration biopsy of HCC is a safe and useful tool that can be used to evaluate the response to proton irradiation. In particular, MIB-1 LI may provide additional information to assess the therapeutic response of HCC during the early post-irradiated period.

Clinical features of gastroduodenal injury associated with long-term low-dose aspirin therapy.

Low-dose aspirin (LDA) is clinically used for the prevention of cardiovascular and cerebrovascular events with the advent of an aging society. On the other hand, a very low dose of aspirin (10 mg daily) decreases the gastric mucosal prostaglandin levels and causes significant gastric mucosal damage. The incidence of LDA-induced gastrointestinal mucosal injury and bleeding has increased. It has been noticed that the incidence of LDA-induced gastrointestinal hemorrhage has increased more than that of non-aspirin non-steroidal anti-inflammatory drug (NSAID)-induced lesions. The pathogenesis related to inhibition of cyclooxygenase (COX)-1 includes reduced mucosal flow, reduced mucus and bicarbonate secretion, and impaired platelet aggregation. The pathogenesis related to inhibition of COX-2 involves reduced angiogenesis and increased leukocyte adherence. The pathogenic mechanisms related to direct epithelial damage are acid back diffusion and impaired platelet aggregation. The factors associated with an increased risk of upper gastrointestinal (GI) complications in subjects taking LDA are aspirin dose, history of ulcer or upper GI bleeding, age > 70 years, concomitant use of non-aspirin NSAIDs including COX-2-selective NSAIDs, and Helicobacter pylori (H. pylori) infection. Moreover, no significant differences have been found between ulcer and non-ulcer groups in the frequency and severity of symptoms such as nausea, acid regurgitation, heartburn, and bloating. It has been shown that the ratios of ulcers located in the body, fundus and cardia are significantly higher in bleeding patients than the ratio of gastroduodenal ulcers in patients taking LDA. Proton pump inhibitors reduce the risk of developing gastric and duodenal ulcers. In contrast to NSAID-induced gastrointestinal ulcers, a well-tolerated histamine H2-receptor antagonist is reportedly effective in prevention of LDA-induced gastrointestinal ulcers. The eradication of H. pylori is equivalent to treatment with omeprazole in preventing recurrent bleeding. Continuous aspirin therapy for patients with gastrointestinal bleeding may increase the risk of recurrent bleeding but potentially reduces the mortality rates, as stopping aspirin therapy is associated with higher mortality rates. It is very important to prevent LDA-induced gastroduodenal ulcer complications including bleeding, and every effort should be exercised to prevent the bleeding complications.

Bile acid malabsorption deactivates pregnane X receptor in patients with Crohn's disease.

BACKGROUND: Recent studies have suggested that the downregulation of pregnane X receptor (PXR) may contribute to the susceptibility and exacerbation of Crohn's disease (CD). Because bile acid malabsorption is one of the features of CD and bile acids are potential activators of PXR, we explored the relationship between bile acid malabsorption and PXR activities in patients with CD. METHODS: Twenty-one patients with CD (4 ileal-resected and 17 nonresected), 10 with ulcerative colitis (UC), and 26 healthy controls were studied. Serum biomarkers for the activity of CYP3A4, a target gene of PXR, and for cholesterol and bile acid metabolism were quantified by liquid chromatography-tandem mass spectrometry or enzyme-linked immunosorbent assay. RESULTS: The concentrations of 4ß-hydroxycholesterol (4ß-HC), a known marker for CYP3A4 activity, and those of 25-hydroxycholesterol (25-HC), another metabolite by CYP3A4, were significantly reduced in all patients with CD, especially in those with the history of ileal resection. The concentration of 7α-hydroxy-4-cholesten-3-one (C4), a marker for hepatic bile acid biosynthesis, was significantly elevated, whereas the levels of fibroblast growth factor 19 (FGF19), a marker for intestinal bile acid flux, were reduced in patients with CD compared with patients with UC and controls. A significant negative correlation was observed between 4ß-HC or 25-HC and C4 concentrations in all patients with CD. CONCLUSIONS: The degree of bile acid malabsorption was closely associated with the deactivation of PXR in CD. Enterohepatic circulation of bile acids is a key factor for preservation of baseline activity of hepatointestinal PXR.

Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid.

UNLABELLED: Bezafibrate is a widely used hypolipidemic agent and is known as a ligand of the peroxisome proliferator-activated receptors (PPARs). Recently this agent has come to be recognized as a potential anticholestatic medicine for the treatment of primary biliary cirrhosis (PBC) that does not respond sufficiently to ursodeoxycholic acid (UDCA) monotherapy. The aim of this study was to explore the anticholestatic mechanisms of bezafibrate by analyzing serum lipid biomarkers in PBC patients and by cell-based enzymatic and gene expression assays. Nineteen patients with early-stage PBC and an incomplete biochemical response to UDCA (600 mg/day) monotherapy were treated with the same dose of UDCA plus bezafibrate (400 mg/day) for 3 months. In addition to the significant improvement of serum biliary enzymes, immunoglobulin M (IgM), cholesterol, and triglyceride concentrations in patients treated with bezafibrate, reduction of 7α-hydroxy-4-cholesten-3-one (C4), a marker of bile acid synthesis, and increase of 4ß-hydroxycholesterol, a marker of CYP3A4/5 activity, were observed. In vitro experiments using human hepatoma cell lines demonstrated that bezafibrate controlled the target genes of PPARα, as well as those of the pregnane X receptor (PXR); down-regulating CYP7A1, CYP27A1, and sinusoidal Na(+) /taurocholate cotransporting polypeptide (NTCP), and up-regulating CYP3A4, canalicular multidrug resistance protein 3 (MDR3), MDR1, and multidrug resistance-associated protein 2 (MRP2). CONCLUSION: Bezafibrate is a dual PPARs/PXR agonist with potent anticholestatic efficacy in early-stage PBC patients with an incomplete biochemical response to UDCA monotherapy.