RESUMEN
Increasing evidence suggests that, in addition to a loss of tolerance, bile acid (BA) modulates the natural history of primary biliary cholangitis (PBC). We focused on the impacts of dietary changes on the immunopathology of PBC, along with alterations in BA composition and gut microbiota. In this study, we have taken advantage of our unique PBC model, a Cyp2c70/Cyp2a12 double knockout (DKO), which includes a human-like BA composition, and develops progressive cholangitis following immunization with the PDC-E2 mimic, 2-octynoic acid (2OA). We compared the effects of a ten-week high-fat diet (HFD) (60 % kcal from fat) and a normal diet (ND) on 2OA-treated DKO mice. Importantly, we report that 2OA-treated DKO mice fed HFD had significantly exacerbated cholangitis, leading to cirrhosis, with increased hepatic expression of Th1 cytokines/chemokines and hepatic fibrotic markers. Serum lithocholic acid (LCA) levels and the ratio of chenodeoxycholic acid (CDCA)-derived BAs to cholic acid-derived BAs were significantly increased by HFD. This was also associated with downregulated expression of key regulators of BA synthesis, including Cyp8b1, Cyp3a11, and Sult2a1. In addition, there were increases in the relative abundances of Acetatifactor and Lactococcus and decreases in Desulfovibrio and Lachnospiraceae_NK4A136_group, which corresponded to the abundances of CDCA and LCA. In conclusion, HFD and HFD-induced alterations in the gut microbiota modulate BA composition and nuclear receptor activation, leading to cirrhotic change in this murine PBC model. These findings have significant implications for understanding the progression of human PBC.
RESUMEN
Taurine has many pharmacological roles on various tissues. The maintenance of abundant taurine content in the mammalian body through endogenous synthesis, in addition to exogenous intake, is the essential factor for morphological and functional maintenances in most tissues. The synthesis of taurine from sulfur-containing amino acids is influenced by various factors. Previous literature findings indicate the influence of the intake of proteins and sulfur-containing amino acids on the activity of the rate-limiting enzymes cysteine dioxygenase and cysteine sulfinate decarboxylase. In addition, the regulation of the activity and expression of taurine-synthesis enzymes by hormones, bile acids, and inflammatory cytokines through nuclear receptors have been reported in liver and reproductive tissues. Furthermore, flavin-containing monooxygenase subtype 1 was recently identified as the taurine-synthesis enzyme that converts hypotaurine to taurine. This review introduces the novel taurine synthesis enzyme and the nuclear receptor-associated regulation of key enzymes in taurine synthesis.
Asunto(s)
Cisteína-Dioxigenasa , Mamíferos , Animales , Cisteína-Dioxigenasa/análisis , Cisteína-Dioxigenasa/metabolismo , Mamíferos/metabolismo , Hígado/metabolismo , Taurina/metabolismo , Taurina/farmacología , Receptores Citoplasmáticos y Nucleares/metabolismo , Aminoácidos/análisis , Aminoácidos/metabolismo , Azufre/análisis , Azufre/metabolismoRESUMEN
Primary biliary cholangitis (PBC) is a classic autoimmune disease due to the loss of tolerance to self-antigens. Bile acids (BA) reportedly play a major role in biliary inflammation and/or in the modulation of dysregulated immune responses in PBC. Several murine models have indicated that molecular mimicry plays a role in autoimmune cholangitis; however, they have all been limited by the relative failure to develop hepatic fibrosis. We hypothesized that species-specific differences in the BA composition between mice and humans were the primary reason for this limited pathology. Here, we aimed to study the impact of human-like hydrophobic BA composition on the development of autoimmune cholangitis and hepatic fibrosis. We took advantage of a unique construct, Cyp2c70/Cyp2a12 double knockout (DKO) mice, which have human-like BA composition, and immunized them with a well-defined mimic of the major mitochondrial autoantigen of PBC, namely 2-octynoic acid (2OA). 2OA-treated DKO mice were significantly exacerbated portal inflammation and bile duct damage with increased Th1 cytokines/chemokines at 8 weeks post-initial immunization. Most importantly, there was clear progression of hepatic fibrosis and increased expression of hepatic fibrosis-related genes. Interestingly, these mice demonstrated increased serum BA concentrations and decreased biliary BA concentrations; hepatic BA levels did not increase because of the upregulation of transporters responsible for the basolateral efflux of BA. Furthermore, cholangitis and hepatic fibrosis were more advanced at 24 weeks post-initial immunization. These results indicate that both the loss of tolerance and the effect of hydrophobic BA are essential for the progression of PBC.
Asunto(s)
Enfermedades Autoinmunes , Colangitis , Cirrosis Hepática Biliar , Humanos , Animales , Ratones , Ácidos y Sales Biliares , Cirrosis Hepática , Inflamación , Autoantígenos , Modelos Animales de EnfermedadRESUMEN
Taurine enhances physical performance; however, the underlying mechanism remains unclear. This study examined the effect of taurine on the overtime dynamics of blood glucose concentration (BGC) during endurance exercise in rats. Male F344 rats were subjected to transient treadmill exercise until exhaustion following 3 weeks of taurine supplementation or non-supplementation (TAU and CON groups). Every 10 min during exercise, BGC was measured in blood collected through cannulation of the jugular vein. Gluconeogenesis-, lipolysis-, and fatty acid oxidation-related factors in the plasma, liver, and skeletal muscles were also analyzed after 120-min run. Exercise time to exhaustion was significantly longer with taurine supplementation. BGC in the two groups significantly increased by 40 min and gradually and significantly decreased toward the respective exhaustion point. The decline in BGC from the peak at 40 min was significantly slower in the TAU group. The time when the once-increased BGC regressed to the 0-time level was significantly and positively correlated with exercise time until exhaustion. At the 120-min point, where the difference in BGC between the two groups was most significant, plasma free fatty acid concentration and acetyl-carnitine and N-acetyltaurine concentrations in skeletal muscle were significantly higher in the TAU group, whereas glycogen and glucogenic amino acid concentrations and G6Pase activity in the liver were not different between the two groups. Taurine supplementation enhances endurance capacity by delaying the decrease in BGC toward exhaustion through increases of lipolysis in adipose tissues and fatty acid oxidation in skeletal muscles during endurance exercise.
Asunto(s)
Glucemia , Resistencia Física , Animales , Glucemia/metabolismo , Suplementos Dietéticos , Masculino , Músculo Esquelético/metabolismo , Ratas , Ratas Endogámicas F344 , Taurina/metabolismo , Taurina/farmacologíaRESUMEN
Deficiency of the functional amino acid-like compound taurine induced in cats by taurine-depleted food was previously shown to significantly decrease the levels of taurine-conjugated bile acids (BAs) and significantly increase the levels of unconjugated BAs, with a significant decrease in total BA concentration in the bile. Because the ratios of primary BAs (cholic acid [CA] and chenodeoxycholic acids [CDCA]) have also been shown to be altered in the bile, taurine has been suggested to play an important role in BA synthesis in the liver. The present study showed that in the liver of taurine-deficient cats, CYP7A1 protein expression and its metabolites (7α-hydroxycholesterol and α-hydroxy-4-cholesten-3-one) were significantly increased and, therefore, the ratio of the CA product in this pathway was decreased. On the other hand, the expression of the mitochondrial CYP27A1 protein and its metabolite 27-hydroxycholesterol (27HC) were significantly decreased in the taurine-deficient liver. Thus, a significantly decreased ratio of CDCA, which is the main product of 27HC, was found. The decreased activity of the CDCA-producing pathway might be related to mitochondrial dysfunction induced by taurine deficiency. In addition, a significant decrease in cholesterol levels in the liver was induced by a decrease in intestinal cholesterol absorption because of decreased hepatic-intestinal circulation of taurine-conjugated BAs. The results of this study showed that taurine deficiency alters both the quality and quantity of BAs through inactivity of the mitochondrial CDCA production pathway caused by impaired mitochondrial function and inhibited the absorption of cholesterol in the intestine.
Asunto(s)
Ácidos y Sales Biliares , Taurina , Animales , Bilis/metabolismo , Ácidos y Sales Biliares/metabolismo , Gatos , Ácido Quenodesoxicólico/metabolismo , Colesterol/metabolismo , Hígado/metabolismo , Taurina/metabolismoRESUMEN
Taurine is an essential nutrient for felines including lions. Various severe symptoms induced by taurine deficiency have been reported for domestic and captive felines. Particularly for captive lions in zoos, little information related to taurine requirements is available. Therefore, this study evaluated the relationship between blood taurine concentration and taurine content in prey feed given at zoos, as well as the composition, types, and conjugation properties of bile acids (BAs) in blood collected repeatedly from four lions housed at three zoos. Blood taurine concentrations in four lions were within the normal range, although individual differences and variations were found. Taurine was abundant in feed supplied at the zoos. A positive correlation between blood taurine concentration and feed amount was observed in lions housed at the same zoo. Approximately 70-80% of the total BA pool was cholic acid, with 50-70% being taurine-conjugated. Individual differences and variations were found. No correlation was found between blood taurine concentration and the compositions of BAs in the blood. Results showed that supply of taurine was sufficient for all lions fed the prey feed. Future studies must be conducted to clarify influences on individual differences, as well as individual variations in blood taurine concentration and blood BA composition.
Asunto(s)
Ácidos y Sales Biliares , Leones , Animales , Gatos , TaurinaRESUMEN
The bile acid (BA) composition in mice is substantially different from that in humans. Chenodeoxycholic acid (CDCA) is an end product in the human liver; however, mouse Cyp2c70 metabolizes CDCA to hydrophilic muricholic acids (MCAs). Moreover, in humans, the gut microbiota converts the primary BAs, cholic acid and CDCA, into deoxycholic acid (DCA) and lithocholic acid (LCA), respectively. In contrast, the mouse Cyp2a12 reverts this action and converts these secondary BAs to primary BAs. Here, we generated Cyp2a12 KO, Cyp2c70 KO, and Cyp2a12/Cyp2c70 double KO (DKO) mice using the CRISPR-Cas9 system to study the regulation of BA metabolism under hydrophobic BA composition. Cyp2a12 KO mice showed the accumulation of DCAs, whereas Cyp2c70 KO mice lacked MCAs and exhibited markedly increased hepatobiliary proportions of CDCA. In DKO mice, not only DCAs or CDCAs but also DCAs, CDCAs, and LCAs were all elevated. In Cyp2c70 KO and DKO mice, chronic liver inflammation was observed depending on the hepatic unconjugated CDCA concentrations. The BA pool was markedly reduced in Cyp2c70 KO and DKO mice, but the FXR was not activated. It was suggested that the cytokine/c-Jun N-terminal kinase signaling pathway and the pregnane X receptor-mediated pathway are the predominant mechanisms, preferred over the FXR/small heterodimer partner and FXR/fibroblast growth factor 15 pathways, for controlling BA synthesis under hydrophobic BA composition. From our results, we hypothesize that these KO mice can be novel and useful models for investigating the roles of hydrophobic BAs in various human diseases.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/genética , Ácidos y Sales Biliares/metabolismo , Sistema Enzimático del Citocromo P-450/genética , Modelos Animales de Enfermedad , Esteroide Hidroxilasas/genética , Animales , Hidrocarburo de Aril Hidroxilasas/deficiencia , Hidrocarburo de Aril Hidroxilasas/metabolismo , Ácidos y Sales Biliares/química , Ácido Quenodesoxicólico/química , Ácido Quenodesoxicólico/metabolismo , Sistema Enzimático del Citocromo P-450/deficiencia , Sistema Enzimático del Citocromo P-450/metabolismo , Femenino , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Esteroide Hidroxilasas/deficiencia , Esteroide Hidroxilasas/metabolismoRESUMEN
Taurine content in the body is maintained by both biosynthesis from sulfur-contained amino acids in the liver and ingestion from usual foods, mainly seafoods and meat. Contrary to the rodents, the maintenance of taurine content in the body depends on the oral taurine ingestion in cats as well as humans because of the low ability of the biosynthesis. Therefore, insufficient of dietary taurine intake increases the risks of various diseases such as blind and expanded cardiomyopathy in the cats. One of the most established physiological roles of taurine is the conjugation with bile acid in the liver. In addition, taurine has effect to increase the expression and activity of bile acid synthesis rate-limiting enzyme CYP7A1. Present study purposed to evaluate the influence of taurine deficiency on bile acids in the cats fed taurine-lacking diet. Adult cats were fed the soybean protein-based diet with 0.15% taurine or without taurine for 30 weeks. Taurine concentration in serum and liver was undetectable, and bile acids in the bile were significantly decreased in the taurine-deficient cats. Taurine-conjugated bile acids in the bile were significantly decreased, and instead, unconjugated bile acids were significantly increased in the taurine-deficient cats. Present results suggested that the taurine may play an important role in the synthesis of bile acids in the liver.
Asunto(s)
Ácidos y Sales Biliares/análisis , Bilis/química , Hígado/fisiopatología , Taurina/deficiencia , Animales , Gatos , DietaRESUMEN
Nuclear receptor farnesoid X receptor activation inhibits fatty acid synthesis through the liver X receptor-α-sterol regulatory element binding protein-1c pathway universally in animals, but also has human-specific crosstalk with the peroxisome proliferator-activated receptor-α. The effects of farnesoid X receptor-ligands on both the synthesis and degradation of fatty liver through nuclear receptor-related regulation were investigated in both human and murine hepatocytes. A fatty liver culture cell model was established using a synthetic liver X receptor-α-ligand (To901317) for both human and mouse non-neoplastic hepatocytes. The hepatocytes were exposed to natural or synthetic farnesoid X receptor-ligands (bile acids, GW4064, obeticholic acid) together with or after To901317. Cellular triglyceride accumulation was significantly inhibited by the farnesoid X receptor-ligands along with inhibition of lipogenic genes and up-regulation of farnesoid X receptor-target small heterodimer partner in both human and mouse cells. The accumulated triglyceride was significantly degraded by the farnesoid X receptor-ligands only in the human cells accompanied with the up-regulations of peroxisome proliferator-activated receptor-α and fatty acid ß-oxidation. Farnesoid X receptor-ligands can be therapeutic agents for treating human fatty liver through dual effects on inhibition of lipogenesis and on enhancement of lipolysis.
RESUMEN
Taurine is metabolized to a novel metabolite, N-acetyltaurine (NAT), through N-acetylation with acetate. Furthermore, NAT production increases when the endogenous production of acetate is elevated in some situations, such as alcohol catabolism and endurance exercise. We have previously reported that both the serum concentration and urinary excretion of NAT from humans were increased after endurance exercise, and that NAT was secreted by cultured skeletal muscle cells exposed to both acetate and taurine. The present study evaluated the hypothesis that NAT is synthesized in the skeletal muscle after endurance exercise. Normal rats were loaded to a transient treadmill running until exhaustion. Serum, skeletal muscle, and liver were collected immediately after the exercise. The NAT concentration in the plasma and in the soleus muscle from the exercised rats was significantly increased compared to that in the samples from the sedentary control rats. There was a significant positive correlation in the NAT concentration between the plasma and soleus muscle. The NAT concentration in the liver was unchanged after the endurance exercise. These results confirm that the significantly increased NAT in both the serum and urine after endurance exercise is derived from NAT synthesis in the skeletal muscle.
Asunto(s)
Músculo Esquelético/metabolismo , Condicionamiento Físico Animal/fisiología , Resistencia Física/fisiología , Taurina/análogos & derivados , Animales , Masculino , Ratas , Ratas Endogámicas F344 , Taurina/metabolismoRESUMEN
Insulin resistance occurs frequently in patients with chronic kidney disease. However, the mechanisms of insulin resistance associated with chronic kidney disease are unclear. It is known that an increase in the mitochondrial acetyl-CoA (AcCoA)/CoA ratio causes insulin resistance in skeletal muscle, and this ratio is regulated by carnitine acetyltransferase that exchanges acetyl moiety between CoA and carnitine. Because excess acetyl moiety of AcCoA is excreted in urine as acetylcarnitine, we hypothesized that retention of acetylcarnitine might be a cause of insulin resistance in chronic kidney disease patients. Serum acetylcarnitine concentrations were measured in chronic kidney disease patients, and were significantly increased with reduction of renal function. The effects of excess extracellular acetylcarnitine on insulin resistance were studied in cultured skeletal muscle cells (C2C12 and human myotubes), and insulin-dependent glucose uptake was significantly and dose-dependently inhibited by addition of acetylcarnitine. The added acetylcarnitine was converted to carnitine via reverse carnitine acetyltransferase reaction, and thus the AcCoA concentration and AcCoA/CoA ratio in mitochondria were significantly elevated. The results suggest that increased serum acetylcarnitine in CKD patients causes AcCoA accumulation in mitochondria by stimulating reverse carnitine acetyltransferase reaction, which leads to insulin resistance in skeletal muscle.
RESUMEN
Oxidative stress and dysregulated cholesterol metabolism are characteristic features of chronic hepatitis C virus infection (CHC). Therefore, we analyzed serum oxysterol profiles in CHC patients and examined the significance of oxysterols in CHC. The concentrations of 7α-hydroxycholesterol, 4ß-hydroxycholesterol and 25-hydroxycholesterol as determined by LC-ESI-MS/MS were significantly elevated by +236%, +29% and +44%, respectively, in CHC patients compared with controls. Moreover, the elevated levels were significantly decreased by anti-viral therapy using PEGylated-interferon and ribavirin for 3 months. In contrast, 24S-hydroxycholesterol, 27-hydroxycholesterol and 7α-hydroxy-4-cholesten-3-one concentrations were not affected by CHC or anti-viral treatment. These results suggest that some oxysterols that are elevated in CHC are produced by cholesterol autoxidation due to oxidative stress or inflammation in the liver. Oxysterols may represent novel targets for the inhibition of disease progression and the prevention of hepatocarcinogenesis in CHC patients.
Asunto(s)
Hepatitis C Crónica/sangre , Hepatitis C Crónica/tratamiento farmacológico , Hidroxicolesteroles/sangre , Antivirales/uso terapéutico , Estudios de Casos y Controles , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Masculino , Persona de Mediana Edad , Estrés Oxidativo , Polietilenglicoles/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Ribavirina/uso terapéutico , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Masas en Tándem/métodosRESUMEN
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.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Bezafibrato/uso terapéutico , Colagogos y Coleréticos/uso terapéutico , Cirrosis Hepática Biliar/tratamiento farmacológico , Ácido Ursodesoxicólico/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anticolesterolemiantes/farmacología , Bezafibrato/farmacología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Citocromo P-450 CYP3A/efectos de los fármacos , Quimioterapia Combinada , Femenino , Humanos , Lípidos/sangre , Hígado/enzimología , Cirrosis Hepática Biliar/sangre , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , PPAR alfa/efectos de los fármacos , Receptor X de Pregnano , Receptores de Esteroides/efectos de los fármacos , Insuficiencia del Tratamiento , Resultado del TratamientoRESUMEN
Taurine (2-aminoethylsulfonic acid) has many physiological and pharmacological functions in most tissues. It is abundantly maintained in the liver by both endogenous biosynthesis and exogenous transport, but is decreased in liver diseases. In the hepatic lobule, there are heterogeneous differences in metabolism between the pericentral (PC) and periportal regions, and the distributions of the biosynthesis capacity and specific taurine transporter expression are predominantly in the PC region. In cases of depletion of hepatic taurine level, serious liver damages were observed in the PC region. Taurine has protective effects against xenobiotics-induced liver damages in the PC region, but not xenobiotics-induced PP region damages. The xenobiotics that injure the PC region are mainly catabolized by NADPH-dependent cytochrome P450 2E1 that is also predominantly expressed in the PC region. Taurine treatment seems to be a useful agent for CYP2E1-related liver diseases with predominant damages in the PC region.
Asunto(s)
Citocromo P-450 CYP2E1/metabolismo , Hepatopatías , Hígado/metabolismo , Taurina/uso terapéutico , Animales , Humanos , Hígado/patología , Hepatopatías/tratamiento farmacológico , Hepatopatías/metabolismo , Hepatopatías/patología , Estrés Oxidativo/efectos de los fármacos , Xenobióticos/efectos adversosRESUMEN
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.
RESUMEN
Taurine abundantly contained in the skeletal muscle has been considered as one of essential factors for the differentiation and growth of skeletal muscles. The previous studies in the taurine transporter knockout mice showed that deficiency of taurine content in the skeletal muscle caused incomplete muscular developments, morphological abnormalities, and exercise abilities. In fetal and neonatal periods, taurine must be an essential amino acid due to no biosynthesis capacity, and therefore, taurine should be endogenously supplied through placenta and maternal milk. In general cell culture condition, taurine contained in the culture medium is absent or few, and therefore, most of cultured cells are in taurine-deficient condition. In the present study, we confirmed, in cultured mouse differentiable myoblast, taurine treatment significantly enhanced the differentiation to myotube in a dose-dependent manner, while these effects were abrogated by inhibitions of taurine transport and Ca(2+) signaling pathway.The present study suggested that exogenous taurine might play a key role on the mature differentiation/growth of the skeletal muscle during development period through Ca(2+) signaling pathway, and therefore, taurine would contribute the muscle recovery after damages.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Células Musculares/citología , Músculo Esquelético/citología , Taurina/farmacología , Animales , Transporte Biológico/efectos de los fármacos , Señalización del Calcio/efectos de los fármacos , Línea Celular , Ratones , Microscopía Fluorescente , Células Musculares/efectos de los fármacos , Células Musculares/metabolismo , Fibras Musculares Esqueléticas/citología , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Mioblastos/citología , Mioblastos/efectos de los fármacos , Mioblastos/metabolismoRESUMEN
Taurine (TAU) has a lot of the biological, physiological, and pharmocological functions including anti-inflammatory and anti-oxidative stress. Although previous studies have appreciated the effectiveness of branched-chain amino acids (BCAA) on the delayed-onset muscle soreness (DOMS), consistent finding has not still convinced. The aim of this study was to examine the additional effect of TAU with BCAA on the DOMS and muscle damages after eccentric exercise. Thirty-six untrained male volunteers were equally divided into four groups, and ingested a combination with 2.0 g TAU (or placebo) and 3.2 g BCAA (or placebo), thrice a day, 2 weeks prior to and 4 days after elbow flexion eccentric exercise. Following the period after eccentric exercise, the physiological and blood biochemical markers for DOMS and muscle damage showed improvement in the combination of TAU and BCAA supplementation rather than in the single or placebo supplementations. In conclusion, additional supplement of TAU with BCAA would be a useful way to attenuate DOMS and muscle damages induced by high-intensity exercise.
Asunto(s)
Aminoácidos de Cadena Ramificada/uso terapéutico , Ejercicio Físico , Conducta Alimentaria , Debilidad Muscular/tratamiento farmacológico , Músculo Esquelético/patología , Taurina/uso terapéutico , Aminoácidos de Cadena Ramificada/administración & dosificación , Aminoácidos de Cadena Ramificada/farmacología , Área Bajo la Curva , Biomarcadores/sangre , Conducta Alimentaria/efectos de los fármacos , Humanos , L-Lactato Deshidrogenasa/sangre , Masculino , Debilidad Muscular/sangre , Debilidad Muscular/enzimología , Músculo Esquelético/efectos de los fármacos , Dimensión del Dolor , Taurina/administración & dosificación , Taurina/farmacología , Adulto JovenRESUMEN
Taurine, the end product in the sulfur-containing amino acid pathway, is conjugated with bile acids (BAs) in the liver. The rate-limiting enzymes in both taurine synthesis and BA conjugation may be regulated by a nucleus receptor, FXR, that promotes BA homeostasis. However, it is controversial because BAs act as natural FXR agonists or antagonists in humans and mice, respectively, due to the species differences in BA synthesis. The present study evaluated the influences of different BA compositions on both pathways in the liver by comparing Cyp2a12-/-/Cyp2c70-/- mice with a human-like BA composition (DKO) and wild-type (WT) mice. The DKO liver contains abundant natural FXR agonistic BAs, and the taurine-conjugated BA proportion and the taurine concentration were significantly increased, while the total BA concentration was significantly decreased compared to those in the WT liver with natural FXR antagonistic BAs. The mRNA expression levels of the enzymes Bacs and Baat in BA aminations and Cdo and Fmo1 in the taurine synthesis, as well as Fxr and its target gene, Shp, were significantly higher in the DKO liver than in the WT liver. The present study, using a model with a human-like BA composition in the liver, confirmed, for the first time in mice, that both the taurine synthesis and BA amidation pathways are upregulated by FXR activation.
RESUMEN
Glucagon levels are elevated in diabetes and some liver diseases. Increased glucagon secretion leads to abnormal stimulation of glucagon receptors (GRs) and consequent elevated glucose production in the liver. Blocking glucagon receptor signaling has been proposed as a potential treatment option for diabetes and other conditions associated with hyperglycemia. Elucidating mechanisms of GR desensitization and downregulation may help identify new drug targets besides GR itself. The present study explores the mechanisms of GR internalization and the role of PKCα, GPCR kinases (GRKs) and ß-arrestins therein. We have reported previously that PKCα mediates GR phosphorylation and desensitization. While the PKC agonist, PMA, did not affect GR internalization when tested alone, it increased glucagon-mediated GR internalization by 25-40% in GR-expressing HEK-293 cells (HEK-GR cells). In both primary hepatocytes and HEK-GR cells, glucagon treatment recruited PKCα to the plasma membrane where it colocalized with GR. We also observed that overexpression of GRK2, GRK3, or GRK5 enhanced GR internalization. In addition, we found that GR utilizes both clathrin- and caveolin-mediated endocytosis in HEK-GR cells. Glucagon triggered translocation of both ß-arrestin1 and ß-arrestin2 from the cytosol to the perimembrane region, and overexpression of ß-arrestin1 and ß-arrestin2 increased GR internalization. Furthermore, both ß-arrestin1 and ß-arrestin2 colocalized with GR and with Cav-1, suggesting the possible involvement of these arrestins in GR internalization.
Asunto(s)
Arrestinas/metabolismo , Quinasas de Receptores Acoplados a Proteína-G/metabolismo , Proteína Quinasa C-alfa/metabolismo , Receptores de Glucagón/metabolismo , Animales , Caveolinas/metabolismo , Membrana Celular/metabolismo , Células Cultivadas , Clatrina/metabolismo , Cricetinae , Endocitosis/fisiología , Glucagón/metabolismo , Células HEK293 , Hepatocitos/metabolismo , Humanos , Masculino , Transporte de Proteínas , beta-ArrestinasRESUMEN
Taurine (2-aminoethanesulfonic acid) is well known to be abundantly contained in almost all the tissues and cells of various mammals, fish, and shellfish [...].