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
To evaluate the effect of dapsone (4,4'-diaminodiphenylsulfone, DDS) on biliary bile salt secretion, we administered the drug to male and female Wistar rats at a dose of 30 mg/kg body wt, twice a day, for 4 days. DDS decreased basal bile flow by about 20% in both male and female rats. In addition, basal biliary bile salt secretion was decreased by the drug in animals from both sexes (about 30% decrease). Bile salt maximum secretory rate, as evaluated by infusing tauroursodeoxycholate at stepwise-increasing rates, was not affected by DDS in either male or female rats, suggesting that the density of canalicular bile salt transporters is preserved. The size of the bile salt pool and the rate of de novo synthesis of bile salts, measured in bile salt-depleted animals, were decreased by about 33 and 35%, respectively; there was no difference in response between males and females. The ability of the ileum to reabsorb bile salts, as estimated by analysis of the expression of the ileal apical sodium-dependent bile salt transporter and of sodium taurocholate transport activity in brush border membrane vesicles, was not affected by DDS in either males or females. Overall, our findings suggest that an impairment of de novo synthesis mediated by a direct inhibition of CYP3A metabolism, rather than a decreased intestinal reabsorption of bile salts, accounts for the decrease in bile salt pool size. The dissociation between alteration of bile secretory function and the oxidative stress induced by DDS, which is known to be relevant only in male rats, is discussed.