RESUMO
Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic and cardiometabolic mortality. The rapidly increasing prevalence of this disease and of its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches to prevent disease progression to advanced fibrosis or cirrhosis and cancer. In recent years, bile acids have emerged as relevant signaling molecules that act at both hepatic and extrahepatic tissues to regulate lipid and carbohydrate metabolic pathways as well as energy homeostasis. Activation or modulation of bile acid receptors, such as the farnesoid X receptor and TGR5, and transporters, such as the ileal apical sodium-dependent bile acid transporter, appear to affect both insulin sensitivity and NAFLD/NASH pathogenesis at multiple levels, and these approaches hold promise as novel therapies. In the present review, we summarize current available data on the relationships of bile acids to NAFLD and the potential for therapeutically targeting bile-acid-related pathways to address this growing world-wide disease. (Hepatology 2017;65:350-362).
Assuntos
Ácidos e Sais Biliares/fisiologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Metabolismo Energético , Glucose/metabolismo , Humanos , Inflamação/etiologia , Metabolismo dos Lipídeos , Fígado , Microbiota , Hepatopatia Gordurosa não Alcoólica/genética , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Receptores Acoplados a Proteínas G , Transdução de SinaisRESUMO
UDCA (ursodeoxycholic acid) is the therapeutic agent most widely used for the treatment of cholestatic hepatopathies. Its use has expanded to other kinds of hepatic diseases, and even to extrahepatic ones. Such versatility is the result of its multiple mechanisms of action. UDCA stabilizes plasma membranes against cytolysis by tensioactive bile acids accumulated in cholestasis. UDCA also halts apoptosis by preventing the formation of mitochondrial pores, membrane recruitment of death receptors and endoplasmic-reticulum stress. In addition, UDCA induces changes in the expression of metabolizing enzymes and transporters that reduce bile acid cytotoxicity and improve renal excretion. Its capability to positively modulate ductular bile flow helps to preserve the integrity of bile ducts. UDCA also prevents the endocytic internalization of canalicular transporters, a common feature in cholestasis. Finally, UDCA has immunomodulatory properties that limit the exacerbated immunological response occurring in autoimmune cholestatic diseases by counteracting the overexpression of MHC antigens and perhaps by limiting the production of cytokines by immunocompetent cells. Owing to this multi-functionality, it is difficult to envisage a substitute for UDCA that combines as many hepatoprotective effects with such efficacy. We predict a long-lasting use of UDCA as the therapeutic agent of choice in cholestasis.
Assuntos
Colagogos e Coleréticos/farmacologia , Colestase/tratamento farmacológico , Ácido Ursodesoxicólico/farmacologia , Animais , Apoptose/efeitos dos fármacos , Ácidos e Sais Biliares/fisiologia , Canalículos Biliares/efeitos dos fármacos , Colagogos e Coleréticos/uso terapêutico , Colestase/patologia , Colestase/fisiopatologia , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ácido Ursodesoxicólico/uso terapêuticoRESUMO
The effects of dapsone (DDS) treatment (30 mg/kg body wt, twice a day, for 4 days) on biliary secretory function, with special emphasis on bile salt independent bile flow (BSIF), were investigated in male and in female Wistar rats. Because DDS is metabolized to its N-hydroxylated parent compound only in male rats, any gender difference in DDS effect can be causally attributed to this metabolite. The two main driving forces for BSIF, the biliary secretion of HCO(3)(-) and glutathione species, were assessed. BSIF was decreased by about 20% in male but not in female rats after DDS treatment. Basal biliary HCO(3)(-) secretion was decreased also by 20% in males. This was associated with a diminished (-37%) expression of the HCO(3)(-) canalicular transporter, anion exchanger 2 (AE2), detected by western blotting. Biliary output of reduced glutathione (GSH) was not modified by DDS irrespective of gender, whereas excretion of oxidized glutathione (GSSG) was increased by 830% in males. This latter finding confirmed a gender-dependent oxidative stress associated with formation of the N-hydroxylated metabolite of DDS. The expression of multidrug resistance-associated protein 2 (Mrp2), a putative transporter of glutathione species, was decreased by 38% as detected by western blotting, clearly dissociating from preserved or increased biliary excretion of GSH and GSSG. In conclusion, our results show an impairment of BSIF by DDS mainly due to a decreased AE2-mediated biliary excretion of HCO(3)(-), formation of the N-hydroxylated metabolite of DDS being a likely mediator. The clinical relevance of these findings is discussed.
Assuntos
Anti-Infecciosos/farmacologia , Ácidos e Sais Biliares/fisiologia , Bile/fisiologia , Dapsona/farmacologia , Animais , Proteínas de Transporte de Ânions/metabolismo , Anti-Infecciosos/farmacocinética , Antiporters/metabolismo , Bicarbonatos/metabolismo , Dapsona/farmacocinética , Feminino , Hidroxilação , Masculino , Metemoglobina/metabolismo , Proteínas Mitocondriais/metabolismo , Ratos , Ratos Wistar , Proteínas Ribossômicas/metabolismo , Proteínas SLC4A , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMO
Colchicine, a microtubule-disrupting agent, induces hepatotoxicity in experimental animals at the doses commonly employed to explore vesicular transport in the liver. The effect of manipulations of the bile salt pool on colchicine-induced hepatotoxicity was studied in rats to determine the role of bile salts in this phenomenon. Leakage of enzyme markers of liver-cell damage into plasma and bile induced by colchicine pre-treatment displayed a sigmoidal log dose-effect curve, the half-maximal effect being reached at 0.12 micromol per 100 g body wt. Lumicolchicine, instead, showed no harmful effect. Maximal increment of biliary LDH discharge induced by colchicine was reduced from 950 +/- 124% to 216 +/- 29% by bile diversion leading to a marked reduction in bile salt output, and this parameter was further decreased to 100 +/- 13% and 157 +/- 39% by subsequent repletion of the bile salt pool with the hydrophilic bile salts taurodehydrocholate and tauroursodeoxycholate, respectively. Conversely, infusion of taurocholate into non-bile salt depleted, colchicine-treated rats led to cholestasis and massive discharge of enzymes into both blood and bile. Our data show conclusively that colchicine-induced hepatotoxicity depends on the magnitude and composition of the bile salt flux traversing the liver. They also support the view that functional integrity of vesicular mechanisms presumably involved in membrane repair are indispensable to protect the hepatocytes from the damaging effect of bile salts during normal bile formation.
Assuntos
Ácidos e Sais Biliares/metabolismo , Colchicina/toxicidade , Supressores da Gota/toxicidade , Fígado/efeitos dos fármacos , Fosfatase Alcalina/sangue , Animais , Ácidos e Sais Biliares/fisiologia , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Isomerismo , L-Lactato Desidrogenase/sangue , Fígado/patologia , Lumicolchicinas/toxicidade , Masculino , Ratos , Ratos Wistar , Ácido Tauroquenodesoxicólico/metabolismo , Ácido Taurocólico/análogos & derivados , Ácido Taurocólico/metabolismoRESUMO
UNLABELLED: Absence of bile salts in the intestinal lumen of jaundiced patients is associated to bacterial overgrowth and systemic endotoxemia. These bile salts, however, did not show significant influence on aerobic and facultative intestinal bacteria. The increasing bacterial colonization may be due to depressed intestinal motor response. PURPOSE: To evaluate the influence of bile salts on intestinal motor response in presence of obstructive jaundice. METHODS: We studied in vitro the motor response of ileal segments of 30 Holtzman rats divided into three groups (n = 10): washed ileum, intraluminal bile salts and exogenous oral bile salts administred during six days. Five animals of each group were submitted to sham operation and the other five were submitted to ligation and section of the common bile duct. A four centimeter ileal segment was isolated and studied through a dose-response assay with acetylcholine in an organ chamber. RESULTS: The results showed an increased ileal affinity to acetylcholine in presence of intraluminal bile salts. CONCLUSION: The intraluminal bile salts appear to exert in vitro a stimulatory effect on ileal motility.
Assuntos
Acetilcolina/farmacologia , Ácidos e Sais Biliares/fisiologia , Colestase/fisiopatologia , Motilidade Gastrointestinal/efeitos dos fármacos , Íleo/fisiologia , Animais , Colestase/tratamento farmacológico , Colestase/etiologia , Relação Dose-Resposta a Droga , Feminino , Técnicas In Vitro , Ratos , Ratos Sprague-DawleyRESUMO
Nesta revisao sao explicados cada um dos quatro mecanismos de defesa da bile contra a infecçao por microorganismos patógenos, bem como suas açoes integradas. Nesse contexto, incluem-se as barreiras anatômicas (complexos unitivos e esfíncter de Oddid), os mecanismos físicos (fluxo biliar e muco), os fatores químicos (sais biliares) e os mecanismos imunológicos (células de Kupffer e imunoglobulina A secretada). A quebra do funcionamento harmônico desses mecanismos pode levar a sérias infecçoes. Nesse sentido, o aumento da pressao intra-biliar (causada por obstruçao parcial ou completa do fluxo biliar) e doenças do parênquima hepático desempenham papel fundamental. Dessa forma, confirma-se a importância da preservaçao desses mecanismos de defesa no indivíduo saudável.
Assuntos
Sistema Biliar/imunologia , Doenças Biliares/imunologia , Infecções Bacterianas/imunologia , Ácidos e Sais Biliares/fisiologia , Bile/metabolismo , Sistema Biliar/microbiologia , Doenças Biliares/microbiologia , Esfíncter da Ampola Hepatopancreática/imunologia , Imunoglobulinas/metabolismo , Infecções Bacterianas/microbiologia , Muco/metabolismoRESUMO
Biliary stones constitute an important issue in public health, until recently treated exclusively by surgical means. In the western world 80-90 percent of stones are composed of cholesterol, secondary to abnormalities in cholesterol and lipoprotein metabolism. In the last two decades significant advances in the treatment of this problem have been made, such as medical dissolution and extracorporeal lithotripsy. The most significant risk factors are: obesity, rapid weight loss, female sex, pregnancy, diabetes, hypertriglyceridemia, estrosalts derived from cholesterol are hydrophylic sterols that are essential to micelle formation. The predominance of the hydrophylic domain makes them amphophylic. Primary bile salts: cholate and deoxycholate are synthetized in the liver; secondary bile salts: deoxycholate and lithocholate derived from primary ones by bacterial transformation in the gut; tertiary bile salts: ursodeoxycholate and sulpholithocholate derived from secondary salts by bacterial action. Lecithin is the main phospholipid in bile, its main fuction is to solubilize cholesterol associated to bile salts. Micelles are complex structures made of cholesterol, lecithin and bile salts. Experimentally a triangular diagram has been designed representing molar concentrations of cholesterol, lecithin and bile salts. This diagram facilitates the understanding of biliary stones formation. Changing is components keeping constant total lipids, identifics several phases essential in stones formation, such as the micellar phase and the metastable phase. Supersaturated bile results from excess of cholesterol or deficiency of bile salts, and represents the initial abnormality that predispose to stones formation...
Assuntos
Humanos , Ácidos e Sais Biliares/efeitos adversos , Ácidos e Sais Biliares/fisiologia , Colelitíase/complicações , Colelitíase/diagnóstico , Colelitíase/tratamento farmacológico , Colelitíase/epidemiologia , Colelitíase/etiologia , Colelitíase/mortalidade , Colelitíase/patologia , Colelitíase/fisiopatologia , Colelitíase/cirurgia , Colelitíase/terapia , Colesterol/efeitos adversos , Colesterol/fisiologiaRESUMO
The main factors involved in the impairment of formation of the bile salt-independent bile flow (BSIF) in streptozotocin (SZ)-treated rats were examined. Twenty-four hours after SZ injection (50 mg/kg body wt, i.v.) bile flow, bile salt output and biliary excretion of the major inorganic electrolytes (sodium, chloride and bicarbonate) were significantly diminished. The relationship between bile flow and bile salt output obtained during the administration of sodium taurocholate at stepwise-increasing rates indicated that bile salt-independent bile flow (y-intercept) was diminished by 37% in SZ-treated rats. The relationship between electrolyte output and bile salt output showed that the fractions of sodium, chloride and bicarbonate excreted independently of bile salt (y-intercept) decreased to 59%, 47% and 67% of the control values respectively, while the amount of electrolyte secreted per unit of bile salt secreted was unaffected in SZ-treated rats. The hepatic activity of Na+,K(+)-adenosine triphosphatase (Na+,K(+)-ATPase) was decreased by 59% (P less than 0.05) in SZ-treated rats. Nicotinamide administered prior to SZ prevented the hyperglycemia indicative of SZ-induced diabetes, but had no effect on the decrease in Na+,K(+)-ATPase activity caused by the drug. These results suggest that SZ itself, and not its diabetogenic effect, decreases the BSIF by a mechanism that involves impairment of the biliary electrolyte excretion, which could be the result of the inhibition of the hepatic Na+,K(+)-ATPase activity.
Assuntos
Bile/efeitos dos fármacos , Doença Hepática Induzida por Substâncias e Drogas , Eletrólitos/metabolismo , Estreptozocina/farmacologia , Animais , Bile/metabolismo , Ácidos e Sais Biliares/fisiologia , Fígado/enzimologia , Hepatopatias/metabolismo , Hepatopatias/fisiopatologia , Masculino , Ratos , Ratos Endogâmicos , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidoresRESUMO
The purpose of this study was to determine whether adaptive cytoprotection of gastric mucosa could be demonstrated with concentrations of bile acid, which is normally found in the human stomach, and whether cyclooxygenase inhibition, in turn, could blunt the response. Surface epithelial cell exfoliation and ion fluxes were used as end points. A transduodenal gastric cannula was placed, and the pylorus/gastroesophageal junction was ligated in adult male Sprague-Dawley rats that had been anesthetized. In experiment 1 (N = 30), rat stomachs were exposed for 15 minutes to 5 ml of either a neutral test solution (160 mmol/L NaCl, pH 7) or 1 mmol/L acidified taurocholate (ATC) (100 mmol/L HCl, 60 mmol/L NaCl, 1 mmol/L taurocholic acid; pH 1.2). All rats were subsequently exposed for 15 minutes to 5 mmol/L ATC during which time mucosal injury was assessed by measuring net flux of H+, Na+, and K+, volume, and DNA efflux. In experiment 2 (N = 35), all stomachs were pretreated for 15 minutes with 1 mmol/L ATC before mucosal injury with 5 mmol/L ATC (15 minutes). Eighteen rats were pretreated with indomethacin (5 mg/kg) subcutaneously 75 minutes before the experiment was begun, and the same parameters were measured. Pretreatment of rat gastric mucosa with 1 mmol/L ATC significantly attenuated the mucosal injury that was seen with subsequent exposure to 5 mmol/L ATC, resulting in significantly (p less than 0.05) less luminal H+ loss (-16 +/- 4 vs -32 +/- 4 mEq/15 min) and DNA efflux (181 +/- 21 vs 270 +/- 25 micrograms/15 min) than the nonadapted group. Indomethacin pretreatment significantly attenuated the adaptive protective response, resulting in greater loss of H+ (-29 +/- 4 vs -18 +/- 3) and DNA efflux (190 +/- 35 vs 110 +/- 18, both p less than 0.05) after exposure to 5 mmol/L ATC. These studies demonstrate that adaptive cytoprotection of gastric mucosa occurs with physiologic concentrations of an irritant that is normally present in the stomach. Indomethacin blunts this effect, which suggests that adaptive cytoprotection in this setting may be mediated by production of endogenous prostaglandins.
Assuntos
Adaptação Fisiológica , Ácidos e Sais Biliares/fisiologia , Mucosa Gástrica/fisiologia , Ácidos , Animais , Mucosa Gástrica/citologia , Mucosa Gástrica/patologia , Indometacina/farmacologia , Masculino , Concentração Osmolar , Ratos , Ratos Endogâmicos , Ácido Taurocólico/farmacologiaRESUMO
Control male Wistar rats with intact bile circulation, animals with a bile duct-right ureter fistula, and bile duct-right ureter fistula rats fed taurocholic acid (5.5 mg/day) were maintained on a cholesterol-free pellet diet and pulse labeled subcutaneously with radioactive cholesterol. Bile acid feeding did not interfere with the synthesis of cholesterol by the intestinal mucosa or by the whole body in spite of markedly lowering the production of bile acids. Of the total fecal cholesterol mass in bile fistula animals roughly 25% originated from plasma filtration and 75% was ascribed to local mucosal cholesterol synthesis.