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1.
Arterioscler Thromb Vasc Biol ; 41(6): e284-e298, 2021 06.
Article in English | MEDLINE | ID: mdl-33441025
2.
Eur J Pharmacol ; 888: 173490, 2020 Dec 05.
Article in English | MEDLINE | ID: mdl-32827538

ABSTRACT

Increasing evidence shows that the intestinal tract plays an important role in maintaining urate homeostasis and might be a potential therapeutic target for hyperuricaemia. However, uric acid-lowering drugs available in the clinic do not target intestinal excretion as a therapeutic strategy. We previously reported that mangiferin had potent hypouricaemic effects in hyperuricaemic animals. However, the underlying mechanisms are not completely clear. Here, we investigated the effects of mangiferin on the intestinal excretion of urate and its underlying mechanisms. The data revealed that mangiferin concentration-dependently promoted the intestinal secretion of endogenous urate in in situ intestinal closed loops in normal and hyperuricaemic mice, as well as inhibited the absorption of exogenous uric acid perfused into the intestinal loops in rats. Administration of mangiferin not only decreased the serum urate levels in the hyperuricaemic mice but also increased the protein expression of ATP-binding cassette transporter, subfamily G, member 2 (ABCG2) and inhibited the protein expression of glucose transporter 9 (GLUT 9) in the intestine. These findings suggested that intestinal ABCG2 and GLUT9 might be pivotal and possible action sites for the observed hypouricaemic effects. Moreover, no significant changes in intestinal xanthine oxidoreductase activities were observed, suggesting that mangiferin did not affect intestinal uric acid generation in the hyperuricaemic mice. Overall, promoting intestinal elimination of urate by upregulating ABCG2 expression and downregulating GLUT9 expression might be an important mechanism underlying mangiferin lowering serum uric acid levels. Mangiferin supplementation might be beneficial for the prevention and treatment of hyperuricaemia.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/biosynthesis , Intestinal Elimination/drug effects , Monosaccharide Transport Proteins/biosynthesis , Uric Acid/metabolism , Xanthones/pharmacology , ATP Binding Cassette Transporter, Subfamily G, Member 2/agonists , Animals , Hyperuricemia/drug therapy , Hyperuricemia/metabolism , Intestinal Elimination/physiology , Male , Mice , Monosaccharide Transport Proteins/antagonists & inhibitors , Rats , Rats, Sprague-Dawley , Xanthones/therapeutic use
3.
Poult Sci ; 99(5): 2650-2654, 2020 May.
Article in English | MEDLINE | ID: mdl-32359601

ABSTRACT

Three experiments were conducted to determine ileal P digestibility and excreta P retention values for canola meal (CM) using 3 different types of balance assays. The first experiment was an ad libitum-fed chick experiment which evaluated the effect of phytase on ileal P digestibility and excreta P retention values. Chicks were fed a P-deficient cornstarch-dextrose-45% CM basal diet (0.13% nonphytate P) as diet 1 or that diet plus 125 or 250 FTU/kg of phytase, respectively, from 8 to 21 D of age. The digestibility/retention of P was 38% and phytase linearly increased both ileal digestibility and excreta retention of P (P < 0.05). The second experiment was a precision-fed chick assay conducted to determine ileal digestibility of P in CM at 21 D. Mean ileal P digestibility was determined to be 47.5% in chicks fed 6 g and 40.0% in chicks fed 9 g of CM and the values were not significantly different. Experiment 3 was an ad libitum-fed chick assay to determine ileal P digestibility and excreta P retention for CM with and without increasing levels of dietary supplemental Ca. The chicks were fed P-deficient - dextrose - CM diets containing increasing levels of 13.5, 27, 40.5, or 54% CM, respectively, with Ca:nonphytate P ratio maintained at 2:1 in diets 1-4 and 6:1 in diets 5-8. Based on regression analysis of ileal digesta or excreta P output on dietary P concentration, digestibility/retention of P in CM was 30%. Ileal P digestibility (and to a lesser extent excreta P retention) at 21 D was reduced by increased Ca:P ratio. The results of this study indicated that the 3 balance assays yielded reasonably consistent values of 30-40% for P digestibility/retention and ileal P digestibility was greatly affected by Ca:P ratio.


Subject(s)
6-Phytase/metabolism , Animal Husbandry/methods , Calcium, Dietary/metabolism , Chickens/physiology , Digestion , Intestinal Elimination/drug effects , Phosphorus/physiology , 6-Phytase/administration & dosage , Animal Feed/analysis , Animal Nutritional Physiological Phenomena/drug effects , Animals , Calcium, Dietary/administration & dosage , Diet/veterinary , Dietary Supplements/analysis , Digestion/drug effects , Dose-Response Relationship, Drug , Ileum/physiology , Random Allocation
4.
Food Funct ; 10(12): 7900-7912, 2019 Dec 11.
Article in English | MEDLINE | ID: mdl-31789332

ABSTRACT

Hyperuricemia (HUA) is a metabolic disorder that occurs due to the overproduction or under-excretion of uric acid (UA) and is directly linked to the development of many life-threatening diseases. There is a growing interest among many researchers regarding how to overcome the encumbrance of HUA because conventional drugs are associated with multiple side effects. Thus, the present project has been designed to utilize flavonoids and chlorogenic acid-enriched stevia residue extract (STVRE) to combat HUA. The results show that supplementation with STVRE (200 and 400 mg per kg bw) inhibits the XOD enzyme in serum, duodenum, jejunum, and ileum tissues. Moreover, UA levels in the STVRE groups were also significantly (p < 0.05) decreased in serum, duodenum, jejunum, and ileum tissues and juices. STVRE also improved the intestinal morphology and oxidative biomarkers in duodenum, jejunum, and ileum tissues. Protein and mRNA expressions of ABCG2 were upregulated, whereas GLUT9 was downregulated in the STVRE-treated groups as compared with the model control group. The supplementation of STVRE significantly attenuated hyperuricemia and oxidative stress, upregulated ABCG2 and downregulated GLUT9 (protein and mRNA) expression in hyperuricemic mice. The results of our study revealed that the by-product of stevia has the potential to combat hyperuricemia, and can be used as a functional ingredient in the development of nutraceutical products.


Subject(s)
Hyperuricemia/drug therapy , Intestines/drug effects , Organic Anion Transporters/metabolism , Plant Extracts/administration & dosage , Stevia/chemistry , Uric Acid/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Animals , Chlorogenic Acid/administration & dosage , Chlorogenic Acid/analysis , Flavonoids/administration & dosage , Flavonoids/analysis , Glucose Transport Proteins, Facilitative/genetics , Glucose Transport Proteins, Facilitative/metabolism , Humans , Hyperuricemia/metabolism , Intestinal Elimination/drug effects , Intestines/physiology , Male , Mice , Organic Anion Transporters/genetics , Oxidative Stress/drug effects , Plant Extracts/analysis
5.
Rev. esp. enferm. dig ; 111(12): 946-952, dic. 2019. ilus, tab, graf
Article in English | IBECS | ID: ibc-190539

ABSTRACT

Background: the safety and diagnostic accuracy of colonoscopies depends on the quality of colon cleansing. Several factors have been reported that affect the quality of bowel cleansing, hospitalization being one of them. Aims: the aim of the study was to investigate whether a visual educational leaflet improved the level of cleanliness achieved in hospitalized patients undergoing a colonoscopy and to identify predictors of a poor bowel preparation. Methods: a prospective, single-center, endoscopist-blinded, randomized controlled trial was performed. The intervention group was given a visual educational leaflet and both groups received four liters of polyethylene glycol solution. Demographic data, personal history, reason for admission and indication for colonoscopy, work shift during which the procedure was performed and endoscopy findings were collected. The Boston Bowel Preparation Scale (BBPS) was used to assess the bowel preparation. Results: one hundred and thirty-six patients were included in the study; 51.5% were male, with a mean age of 64.3 +/- 17.6 years. The educational leaflet did not result in a difference in the total BBPS obtained between the standard group and the intervention group (7 [6-9] vs 6 [5.7-9]; p = 0.17). According to the multivariable analysis, the only factors associated with a poor bowel cleansing were heart disease (OR 3.37 [1.34-8.46]; p = 0.010) and colorectal cancer (OR 3.82 [1.26-11.61]; p = 0.018). Conclusion: the use of a visual educational leaflet for the preparation of colonoscopies did not provide a significant improvement in hospitalized patients in our health area. Heart disease was identified as the only predictor of poor preparation for colonoscopy


No disponible


Subject(s)
Humans , Male , Female , Middle Aged , Aged , Aged, 80 and over , Colonoscopy/methods , Pharmaceutical Solutions/pharmacology , Preoperative Care/education , Patient Education as Topic/methods , Intestinal Elimination/drug effects , Inpatients/statistics & numerical data , Clinical Protocols , Prospective Studies , Health Knowledge, Attitudes, Practice
6.
Ecotoxicology ; 28(7): 781-789, 2019 Sep.
Article in English | MEDLINE | ID: mdl-31280383

ABSTRACT

Copper is essential, but can be toxic to aquatic organisms when present in high concentrations. In freshwater crustaceans, copper inhibits enzymes related to ionic and osmoregulation and to the ammonia efflux, that leads to Na+ imbalance and inhibition of ammonia excretion. In the animals inhabiting estuarine or seawater, mechanisms of copper toxicity is not clear, but had been described as disruption of ionregulation and metabolism. To clarify the mechanism of copper toxicity in crustaceans inhabiting variable salinity, this work investigated whether copper affects ammonia excretion and enzymes used for ammonia balance and osmoregulation in the blue crab Callintectes sapidus acclimated to salinity 2 and 30 ppt. To achieve this, juveniles of the blue crab were exposed to 63.5 µg/L of copper at both salinities for 96 h. This is an environmentally realistic copper concentration. Results of ammonia efflux, free amino acids and Na+ concentrations in hemolymph, Na+/K+-ATPase, H+-ATPase and, carbonic anhydrase (CA) activities in gills were consistent with the osmoregulatory pattern adopted by the blue crab, which hyperosmoregulates at salinity 2 ppt and osmoconforms at 30 ppt. At 30 ppt copper reduced free amino acid in hemolymph of crabs, suggesting an effect of the metal on osmotic performance. At 2 ppt, copper significantly increased the H+-ATPase activity involved in ammonia excretion. This may be a compensatory response of crabs to maintain low levels of ammonia in their hemolymph; which can be increased by copper exposure. Results presented here are useful for the improvement of the Biotic Ligand Model (BLM) to predict copper toxicity for saltwater environments.


Subject(s)
Ammonia/metabolism , Brachyura/drug effects , Copper/toxicity , Osmoregulation/drug effects , Salinity , Animals , Brachyura/enzymology , Brachyura/metabolism , Intestinal Elimination/drug effects
7.
Methodist Debakey Cardiovasc J ; 15(1): 70-76, 2019.
Article in English | MEDLINE | ID: mdl-31049152

ABSTRACT

Besides the well-known hepatobiliary pathway of cholesterol excretion into the feces, transintestinal cholesterol excretion (TICE) is a second major pathway through which cholesterol is disposed from the body. In the process of TICE, cholesterol is taken up from lipoprotein particles at the basolateral side of the enterocyte and translocates towards the apical side of the enterocyte. At the apical side, the ATP-binding cassette transporters G5 and G8 form a heterodimer that transports cholesterol into the intestinal lumen. A substantial amount of the secreted cholesterol is likely reabsorbed by the cholesterol influx transporter Niemann-Pick C1-Like 1 (NPC1L1) since recent data indicate that inhibition of NPC1L1 increases the efficacy of TICE for disposal of cholesterol via the feces. The pathways and proteins involved in intracellular cholesterol trafficking in the enterocyte have not yet been identified. Therefore, in addition to discussing known mediators of TICE, this review will also examine potential candidates involved in cholesterol translocation in the enterocyte. Both the cholesterol reuptake and efflux pathways can be influenced by pharmaceutical means; thus, the TICE pathway is a very attractive target to increase cholesterol excretion from the body and prevent or mitigate atherosclerotic cardiovascular disease.


Subject(s)
Anticholesteremic Agents/therapeutic use , Cardiovascular Diseases/prevention & control , Cholesterol/blood , Dyslipidemias/drug therapy , Enterocytes/drug effects , Intestinal Elimination/drug effects , Membrane Transport Proteins/drug effects , Animals , Anticholesteremic Agents/adverse effects , Biomarkers/blood , Cardiovascular Diseases/blood , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Down-Regulation , Dyslipidemias/blood , Dyslipidemias/diagnosis , Dyslipidemias/epidemiology , Enterocytes/metabolism , Feces/chemistry , Humans , Membrane Transport Proteins/metabolism
8.
PLoS One ; 14(12): e0226918, 2019.
Article in English | MEDLINE | ID: mdl-31891613

ABSTRACT

Recently, extensive efforts have been made to understand the importance of the extra-renal uric acid (UA) excretion pathways and their contribution to UA-related diseases. However, the method typically used to measure UA concentrations in the intestinal lumen is difficult to real time and dynamic analysis. In this study, UA excretion in the rat intestinal lumen was measured in real time using an electrochemical method. A sensitive electrode to detect UA was constructed using a gold electrode modified with a mixed self-assembled monolayer. Excretion rate of UA in the intestine was calculated using time course data. A decrease in UA excretion rate was observed in the intestine after administration of serum UA-lowering drugs (benzbromarone, febuxostat, and topiroxostat). Inhibition of ATP-binding cassette transporter G2 (ABCG2) which has been reported as an important exporter of UA was suggested by administration of these drugs. On the other hand, an increase in excretion rate of UA was observed in the intestine of 5/6 nephrectomy rats. Upregulation of mRNA expression of the UA transporter organic anion transporter OAT3, which is related to the secretion at the basal membrane, suggested an enhancement of UA excretion by ABCG2, a high-capacity UA exporter. Observed urate excretion dynamics and mRNA expression of UA transporters in the intestine upon administration of serum UA-lowering drugs and 5/6 nephrectomy improve our understanding of the underlying mechanisms of intestinal UA excretion.


Subject(s)
Gout Suppressants/pharmacology , Hyperuricemia/drug therapy , Intestinal Elimination/drug effects , Intestinal Mucosa/metabolism , Uric Acid/analysis , ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Animals , Cardiovascular Diseases/etiology , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/prevention & control , Disease Models, Animal , Humans , Hyperuricemia/complications , Hyperuricemia/metabolism , Kidney Diseases/etiology , Kidney Diseases/metabolism , Kidney Diseases/prevention & control , Male , Nephrectomy/adverse effects , Organic Anion Transporters, Sodium-Independent/metabolism , Rats , Renal Elimination , Up-Regulation , Uric Acid/metabolism
9.
Pharmacol Rep ; 70(1): 172-177, 2018 Feb.
Article in English | MEDLINE | ID: mdl-29367104

ABSTRACT

BACKGROUND: The effects of farnesoid X receptor (FXR) antagonists on plasma lipid profile in mice have not been investigated thus far. The aim of this study was to investigate the antidyslipidemic effects of an FXR antagonist in dyslipidemic mice, and to clarify the mechanisms underlying the lipid modulatory effect. METHODS: Compound-T0 (1-100 mg/kg) was orally administered to C57BL/6J mice fed a Western-type diet or low-density lipoprotein receptor knockout (LDLR-/-) mice fed a Western-type diet for a week, and plasma lipid levels were investigated. Effects on lipid clearance, hepatic triglyceride secretion after Triton WR-1339 challenge, and intestinal lipid absorption were investigated after multiple dosing. RESULTS: Compound-T0 significantly increased plasma level of non-high-density lipoprotein cholesterol in both C57BL/6 and LDLR-/- mice; in addition, it significantly increased plasma triglyceride level in LDLR-/- mice. Compound-T0 failed to enhance the clearance of 3,3'-dioctadecylindocarbocyanine (DiI)-labeled LDL in C57BL/6J mice. Although compound-T0 did not affect triglyceride clearance and hepatic triglyceride secretion, it significantly increased intestinal [3H]cholesterol absorption in LDLR-/- mice. CONCLUSIONS: It was found that the FXR antagonist, compound-T0 exacerbated dyslipidemia in mice because it enhanced intestinal lipid absorption via acceleration of bile acid excretion.


Subject(s)
Benzoates/pharmacology , Dyslipidemias/chemically induced , Lipids/blood , Liver/drug effects , Piperidines/pharmacology , Pyrazoles/pharmacology , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Animals , Bile Acids and Salts/metabolism , Biomarkers/blood , Cholesterol/blood , Disease Models, Animal , Disease Progression , Dose-Response Relationship, Drug , Dyslipidemias/blood , Dyslipidemias/genetics , Genetic Predisposition to Disease , Intestinal Absorption/drug effects , Intestinal Elimination/drug effects , Liver/metabolism , Male , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, LDL/deficiency , Receptors, LDL/genetics , Signal Transduction/drug effects , Time Factors , Triglycerides/blood
10.
J Ethnopharmacol ; 214: 29-36, 2018 Mar 25.
Article in English | MEDLINE | ID: mdl-29233733

ABSTRACT

ETHNOPHARMACOLOGY RELEVANCE: Dioscin, a spirostane glycoside, the rhizoma of Dioscorea septemloba (Diocoreacea) is used for diuresis, rheumatism, and joints pain. Given the poor solubility and stability of Dioscin, we proposed a hypothesis that Dioscin's metabolite(s) are the active substance(s) in vivo to contribute to the reducing effects on serum uric acid levels. AIM OF THE STUDY: The aim of this study is to identify the active metabolite(s) of Dioscin in vivo and to explore the mechanism of its antihyperuricemic activity. MATERIALS AND METHODS: After oral administration of Dioscin in potassium oxonate (PO) induced hyperuricemia rats and adenine-PO induced hyperuricemia mice models, serum uric acid and creatinine levels, clearance of uric acid and creatinine, fractional excretion of uric acid, and renal pathological lesions were determined were used to evaluate the antihyperuricemic effects. Renal glucose transporter-9 (GLUT-9) and organic anion transporter-1 (OAT-1) expressions were analyzed by western blotting method. Renal uric acid excretion was evaluated using stably urate transporter-1 (URAT-1) transfected human epithelial kidney cell line. Intestinal uric acid excretion was evaluated by measuring the transcellular transport of uric acid in HCT116 cells. RESULTS: In hyperuricemia rats, both 25 and 50mg/kg of oral Dioscin decreased serum uric acid levels over 4h. In the hyperuricemia mice, two weeks treatment of Dioscin significantly decreased serum uric acid and creatinine levels, increased clearance of uric acid and creatinine, increased fractional excretion of uric acid, and reduced renal pathological lesions caused by hyperuricemia. In addition, renal GLUT -9 was significantly down-regulated and OAT-1 was up-regulated in Dioscin treated hyperuricemia mice. Dioscin's metabolite Tigogenin significantly inhibited uric acid re-absorption via URAT1 from 10 to 100µM. Diosgenin and Tigogenin increased uric acid excretion via ATP binding cassette subfamily G member 2 (ABCG2). CONCLUSION: Decreasing effect of Dioscin on serum uric acid level and enhancing effect on urate excretion were confirmed in hyperuricemia animal models. Tigogenin, a metabolite of Dioscin, was identified as an active substance with antihyperuricemic activity in vivo, through inhibition of URAT1 and promotion of ABCG2.


Subject(s)
Dioscorea , Diosgenin/analogs & derivatives , Hyperuricemia/drug therapy , Plant Extracts/pharmacology , Renal Elimination/drug effects , Spirostans/pharmacology , Uric Acid/blood , Uricosuric Agents/pharmacology , Adenine , Animals , Biomarkers/blood , Creatinine/blood , Dioscorea/chemistry , Diosgenin/isolation & purification , Diosgenin/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Glucose Transport Proteins, Facilitative/metabolism , HCT116 Cells , Humans , Hyperuricemia/blood , Hyperuricemia/chemically induced , Intestinal Elimination/drug effects , Intestinal Mucosa/metabolism , Intestines/drug effects , Male , Mice , Organic Anion Transport Protein 1/metabolism , Organic Anion Transporters/genetics , Organic Anion Transporters/metabolism , Organic Cation Transport Proteins/genetics , Organic Cation Transport Proteins/metabolism , Oxonic Acid , Phytotherapy , Plant Extracts/isolation & purification , Plants, Medicinal , Rats, Sprague-Dawley , Spirostans/isolation & purification , Time Factors , Uricosuric Agents/isolation & purification
11.
Arterioscler Thromb Vasc Biol ; 37(5): 990-996, 2017 05.
Article in English | MEDLINE | ID: mdl-28279967

ABSTRACT

OBJECTIVE: Ezetimibe improves cardiovascular outcomes when added to optimum statin treatment. It lowers low-density lipoprotein cholesterol and percent intestinal cholesterol absorption, but the exact cardioprotective mechanism is unknown. We tested the hypothesis that the dominant effect of ezetimibe is to increase the reverse transport of cholesterol from rapidly mixing endogenous cholesterol pool into the stool. APPROACH AND RESULTS: In a randomized, placebo-controlled, double-blind parallel trial in 24 healthy subjects with low-density lipoprotein cholesterol 100 to 200 mg/dL, we measured cholesterol metabolism before and after a 6-week treatment period with ezetimibe 10 mg/d or placebo. Plasma cholesterol was labeled by intravenous infusion of cholesterol-d7 in a lipid emulsion and dietary cholesterol with cholesterol-d5 and sitostanol-d4 solubilized in oil. Plasma and stool samples collected during a cholesterol- and phytosterol-controlled metabolic kitchen diet were analyzed by mass spectrometry. Ezetimibe reduced intestinal cholesterol absorption efficiency 30±4.3% (SE, P<0.0001) and low-density lipoprotein cholesterol 19.8±1.9% (P=0.0001). Body cholesterol pool size was unchanged, but fecal endogenous cholesterol excretion increased 66.6±12.2% (P<0.0001) and percent cholesterol excretion from body pools into the stool increased 74.7±14.3% (P<0.0001), whereas plasma cholesterol turnover rose 26.2±3.6% (P=0.0096). Fecal bile acids were unchanged. CONCLUSIONS: Ezetimibe increased the efficiency of reverse cholesterol transport from rapidly mixing plasma and tissue pools into the stool. Further work is needed to examine the potential relation of reverse cholesterol transport and whole body cholesterol metabolism to coronary events and the treatment of atherosclerosis. CLINICAL TRIALS REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603758.


Subject(s)
Anticholesteremic Agents/administration & dosage , Cholesterol, Dietary/blood , Cholesterol, LDL/blood , Ezetimibe/administration & dosage , Intestinal Elimination/drug effects , Intestines/drug effects , Adult , Aged , Aged, 80 and over , Biomarkers/blood , Double-Blind Method , Feces/chemistry , Female , Healthy Volunteers , Humans , Intestinal Absorption/drug effects , Intestinal Mucosa/metabolism , Male , Middle Aged , Time Factors
12.
Gastroenterology ; 152(5): 1126-1138.e6, 2017 04.
Article in English | MEDLINE | ID: mdl-28065787

ABSTRACT

BACKGROUND & AIMS: The role of the intestine in the maintenance of cholesterol homeostasis increasingly is recognized. Fecal excretion of cholesterol is the last step in the atheroprotective reverse cholesterol transport pathway, to which biliary and transintestinal cholesterol excretion (TICE) contribute. The mechanisms controlling the flux of cholesterol through the TICE pathway, however, are poorly understood. We aimed to identify mechanisms that regulate and stimulate TICE. METHODS: We performed studies with C57Bl/6J mice, as well as with mice with intestine-specific knockout of the farnesoid X receptor (FXR), mice that express an FXR transgene specifically in the intestine, and ABCG8-knockout mice. Mice were fed a control diet or a diet supplemented with the FXR agonist PX20606, with or without the cholesterol absorption inhibitor ezetimibe. Some mice with intestine-specific knockout of FXR were given daily injections of fibroblast growth factor (FGF)19. To determine fractional cholesterol absorption, mice were given intravenous injections of cholesterol D5 and oral cholesterol D7. Mice were given 13C-acetate in drinking water for measurement of cholesterol synthesis. Bile cannulations were performed and biliary cholesterol secretion rates were assessed. In a separate set of experiments, bile ducts of male Wistar rats were exteriorized, allowing replacement of endogenous bile by a model bile. RESULTS: In mice, we found TICE to be regulated by intestinal FXR via induction of its target gene Fgf15 (FGF19 in rats and human beings). Stimulation of this pathway caused mice to excrete up to 60% of their total cholesterol content each day. PX20606 and FGF19 each increased the ratio of muricholate:cholate in bile, inducing a more hydrophilic bile salt pool. The altered bile salt pool stimulated robust secretion of cholesterol into the intestinal lumen via the sterol-exporting heterodimer adenosine triphosphate binding cassette subfamily G member 5/8 (ABCG5/G8). Of note, the increase in TICE induced by PX20606 was independent of changes in cholesterol absorption. CONCLUSIONS: Hydrophilicity of the bile salt pool, controlled by FXR and FGF15/19, is an important determinant of cholesterol removal via TICE. Strategies that alter bile salt pool composition might be developed for the prevention of cardiovascular disease. Transcript profiling: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=irsrayeohfcntqx&acc=GSE74101.


Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 8/genetics , Bile Acids and Salts/metabolism , Cholesterol/metabolism , Fibroblast Growth Factors/metabolism , Intestinal Elimination/genetics , Intestinal Mucosa/metabolism , Lipoproteins/genetics , Receptors, Cytoplasmic and Nuclear/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 8/metabolism , Animals , Anticholesteremic Agents/pharmacology , Benzoates/pharmacology , Bile Ducts , Ezetimibe/pharmacology , Intestinal Elimination/drug effects , Intestinal Mucosa/drug effects , Intestines/drug effects , Isoxazoles/pharmacology , Lipoproteins/metabolism , Male , Mice , Mice, Knockout , Mice, Transgenic , Rats , Rats, Wistar , Receptors, Cytoplasmic and Nuclear/agonists
13.
J Lipid Res ; 57(8): 1455-64, 2016 08.
Article in English | MEDLINE | ID: mdl-27313057

ABSTRACT

Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis. Statins reduce plasma cholesterol levels, but whether this is actually caused by inhibition of de novo cholesterol synthesis has not been clearly established. Using three different statins, we investigated the effects on cholesterol metabolism in mice in detail. Surprisingly, direct measurement of whole body cholesterol synthesis revealed that cholesterol synthesis was robustly increased in statin-treated mice. Measurement of organ-specific cholesterol synthesis demonstrated that the liver is predominantly responsible for the increase in cholesterol synthesis. Excess synthesized cholesterol did not accumulate in the plasma, as plasma cholesterol decreased. However, statin treatment led to an increase in cholesterol removal via the feces. Interestingly, enhanced cholesterol excretion in response to rosuvastatin and lovastatin treatment was mainly mediated via biliary cholesterol secretion, whereas atorvastatin mainly stimulated cholesterol removal via the transintestinal cholesterol excretion pathway. Moreover, we show that plasma cholesterol precursor levels do not reflect cholesterol synthesis rates during statin treatment in mice. In conclusion, cholesterol synthesis is paradoxically increased upon statin treatment in mice. However, statins potently stimulate the excretion of cholesterol from the body, which sheds new light on possible mechanisms underlying the cholesterol-lowering effects of statins.


Subject(s)
Cholesterol/biosynthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Liver/metabolism , Lovastatin/pharmacology , Animals , Cholesterol/blood , Drug Evaluation, Preclinical , Gene Expression/drug effects , Glutarates/metabolism , Hypercholesterolemia/blood , Hypercholesterolemia/drug therapy , Intestinal Elimination/drug effects , Intestine, Small/drug effects , Intestine, Small/metabolism , Liver/drug effects , Male , Mice, Inbred C57BL
14.
Biochem Pharmacol ; 97(1): 89-98, 2015 Sep 01.
Article in English | MEDLINE | ID: mdl-26119820

ABSTRACT

The prevalence of hyperuricemia/gout increases with aging. However, the effect of aging on function for excretion of uric acid to out of the body has not been clarified. We found that ileal uric acid clearance in middle-aged rats (11-12 months) was decreased compared with that in young rats (2 months). In middle-aged rats, xanthine oxidase (XO) activity in the ileum was significantly higher than that in young rats. Inosine-induced reactive oxygen species (ROS), which are derived from XO, also decreased ileal uric acid clearance. ROS derived from XO decreased the active homodimer level of breast cancer resistance protein (BCRP), which is a uric acid efflux transporter, in the ileum. Pre-administration of allopurinol recovered the BCRP homodimer level, resulting in the recovering ileal uric acid clearance. Moreover, we investigated the effects of ROS derived from XO on BCRP homodimer level directly in Caco-2 cells using hypoxanthine. Treatment with hypoxanthine decreased BCRP homodimer level. Treatment with hypoxanthine induced mitochondrial dysfunction, suggesting that the decreasing BCRP homodimer level might be caused by mitochondrial dysfunction. In conclusion, ROS derived from XO decrease BCRP homodimer level, resulting in suppression of function for uric acid excretion to the ileal lumen. ROS derived from XO may cause the suppression of function of the ileum for the excretion of uric acid with aging. The results of our study provide a new insight into the causes of increasing hyperuricemia/gout prevalence with aging.


Subject(s)
ATP-Binding Cassette Transporters/antagonists & inhibitors , Aging , Intestinal Mucosa/metabolism , Neoplasm Proteins/antagonists & inhibitors , Reactive Oxygen Species/metabolism , Uric Acid/metabolism , Xanthine Oxidase/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/chemistry , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Allopurinol/pharmacology , Allopurinol/therapeutic use , Animals , Caco-2 Cells/drug effects , Caco-2 Cells/metabolism , Dimerization , Enzyme Induction/drug effects , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Gout Suppressants/pharmacology , Gout Suppressants/therapeutic use , Humans , Hyperuricemia/chemically induced , Hyperuricemia/metabolism , Hyperuricemia/prevention & control , Hypoxanthine/pharmacology , Ileum/drug effects , Ileum/growth & development , Ileum/metabolism , Inosine/toxicity , Intestinal Elimination/drug effects , Intestinal Mucosa/drug effects , Intestinal Mucosa/growth & development , Male , Mitochondria/drug effects , Mitochondria/enzymology , Mitochondria/metabolism , Neoplasm Proteins/chemistry , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Rats, Wistar , Reactive Oxygen Species/agonists , Reactive Oxygen Species/antagonists & inhibitors , Xanthine Oxidase/antagonists & inhibitors , Xanthine Oxidase/chemistry
15.
J Anim Sci ; 92(11): 4964-71, 2014 Nov.
Article in English | MEDLINE | ID: mdl-25349345

ABSTRACT

Fructan supplementation of a commercially available canned cat food was evaluated using senior (≥ 9 yr) cats to assess nitrogen (N) partitioning in excreta and stool metabolite and microbiota concentrations. Oligofructose (OF) or SynergyC (OF+IN) were added to the diet individually at 1% (dry weight basis). Cats were acclimated to the control diet for 7 d and then were randomly assigned to 1 of 3 treatment groups for 21 d (n = 6). Feces and urine were collected on d 22 through 28. No differences were observed in food intake; fecal output, DM percentage, score, pH, or short- or branched-chain fatty acids, fecal and urinary ammonia output, urinary felinine concentrations, or N retention. Supplemental OF+IN tended to decrease N digestibility (P = 0.102) and Bifidobacteria spp. (P = 0.073) and decrease fecal indole (P < 0.05), tyramine (P < 0.05), and Escherichia coli (P < 0.05) concentrations. Both fructan-supplemented treatments decreased (P < 0.05) fecal histamine concentrations. The tendency to a lower apparent N digestibility was likely due to increased colonic microbial protein synthesis of fructan-supplemented cats. Fructan supplementation may benefit senior cats as it modulates stool odor-forming compounds and decreases some protein catabolites and pathogenic gut microbiota concentrations without affecting N retention.


Subject(s)
Cats/metabolism , Feces/microbiology , Fructans/pharmacology , Microbiota , Nitrogen/metabolism , Ammonia/metabolism , Animals , Bifidobacterium/isolation & purification , Dietary Supplements , Eating/drug effects , Eating/physiology , Escherichia coli/isolation & purification , Feces/chemistry , Female , Fructans/administration & dosage , Intestinal Elimination/drug effects , Intestinal Elimination/physiology , Male , Nitrogen/analysis
16.
Xenobiotica ; 44(6): 489-97, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24274355

ABSTRACT

1. Although valuable in vitro models exist to study drug elimination from the systemic circulation, more integrated models may improve mechanistic insight in a biorelevant setting. 2. This study aimed to explore (1) intestinal and biliary excretion of the HIV protease inhibitor darunavir and its impact on systemic disposition and (2) to evaluate to what extent findings in an in situ excretion model in rat can be captured by individual in vitro models. 3. Contemporary in vitro models were applied to study intestinal and hepatobiliary disposition of darunavir and data were compared with findings in the in situ excretion model. 4. Both in situ and in vitro experiments demonstrated significant metabolism of darunavir, which could be strongly inhibited by the P450 inhibitor 1-aminobenzotriazole. Using the P-gp inhibitor zosuquidar, P-gp mediated excretion of darunavir from blood towards gastrointestinal lumen was evidenced and this was confirmed by transport studies in Caco-2 cells. Moreover, involvement of P-gp in the biliary excretion of darunavir was also demonstrated in situ. 5. In general, in situ findings corresponded well with in vitro data. The in situ excretion model offers the possibility to gain mechanistic insight in intestinal and hepatobiliary excretion processes and, at the same time, evaluate their impact on the systemic disposition of a compound.


Subject(s)
Hepatobiliary Elimination , Intestinal Elimination , Sulfonamides/pharmacokinetics , Animals , Area Under Curve , Caco-2 Cells , Cell Membrane Permeability/drug effects , Cells, Cultured , Darunavir , Hepatobiliary Elimination/drug effects , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Infusions, Intravenous , Intestinal Elimination/drug effects , Liver/drug effects , Liver/metabolism , Male , Models, Animal , Rats, Sprague-Dawley , Reproducibility of Results , Sulfonamides/administration & dosage , Triazoles/pharmacology
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