RESUMEN
Bile acids (BAs), which are synthesized in the liver and cycled in the enterohepatic circulation, have been recognized as signaling molecules by activating their receptors in the intestine and liver. Serum taurine-conjugated BAs have been shown to be elevated after bariatric surgeries although the postoperative BA profiles within the enterohepatic circulation have not been investigated. Clarification of these profiles could help explain the mechanisms by which bariatric surgery leads to BA profile alterations and subsequent metabolic effects. We performed duodenal-jejunal bypass (DJB), sleeve gastrectomy (SG), and sham procedures in an obese diabetic rat model induced by high-fat diet and streptozotocin. The weight loss and antidiabetic effects were evaluated postsurgery. BA profiles in the systemic serum and within the enterohepatic circulation were analyzed, together with the expression of related BA transporters and enzymes at week 12 after surgery. Compared with sham, SG induced sustained weight loss, and both DJB and SG significantly improved glucose tolerance and insulin sensitivity with enhanced glucagon-like peptide 1 secretion. Similar to changes in the serum, BAs, especially taurine-conjugated species, were also elevated in the enterohepatic circulation (bile and portal vein) after DJB and SG. In addition, the expression of key BA transporters and conjugational enzymes was elevated postoperatively, whereas the enzymes responsible for BA synthesis were decreased. In conclusion, DJB and SG elevated BA levels in the systemic serum and enterohepatic circulation, especially taurine-conjugated species, which likely indicates increased ileal reabsorption and hepatic conjugation rather than synthesis. NEW & NOTEWORTHY Bile acids (BAs) have been implicated as potential mediators of the weight-independent effects of bariatric surgery. For the first time, we discovered that duodenal-jejunal bypass and sleeve gastrectomy elevated BAs, particularly the taurine-conjugated species in the enterohepatic circulation, likely through the promotion of ileal reabsorption and hepatic conjugation rather than BA synthesis. These findings will improve our understanding of BA metabolism after bariatric surgery and their subsequent metabolic effects.
Asunto(s)
Cirugía Bariátrica , Ácidos y Sales Biliares , Circulación Enterohepática/fisiología , Obesidad , Complicaciones Posoperatorias/metabolismo , Taurina/metabolismo , Animales , Cirugía Bariátrica/efectos adversos , Cirugía Bariátrica/clasificación , Cirugía Bariátrica/métodos , Ácidos y Sales Biliares/sangre , Ácidos y Sales Biliares/metabolismo , Glucemia/metabolismo , Peso Corporal/fisiología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Reabsorción Intestinal/fisiología , Obesidad/metabolismo , Obesidad/fisiopatología , Obesidad/cirugía , RatasRESUMEN
AIM: To investigate factors causing diabetes recurrence after sleeve gastrectomy (SG) and duodenal-jejunal bypass (DJB). METHODS: SG and DJB were performed on rats with diabetes induced by high-fat diet (HFD) and streptozotocin (STZ). HFD was used to induce diabetes recurrence at 4 wk postoperatively. Body weight, oral glucose tolerance test, homeostatic model assessment of insulin resistance (HOMA-IR), insulin signaling [IR, insulin receptor substrate (IRS)1, IRS2, phosphatidylinositol 3-kinase and AKT in liver and skeletal muscle], oral glucose stimulated insulin secretion, beta-cell morphology (mass, apoptosis and insulin secretion), glucagon-like peptide (GLP)-1, PYY and ghrelin were compared among SG rats with common low-fat diet (SG-LFD), SG with HFD (SG-HFD), DJB rats with LFD (DJB-LFD), DJB with HFD (DJB-HFD) and sham-operation with LFD (Sham) at targeted postoperative times. RESULTS: SG and DJB resulted in significant improvement in glucose tolerance, lower HOMA-IR, up-regulated hepatic and muscular insulin signaling, higher levels of oral glucose-stimulated insulin secretion, bigger beta-cell mass, higher immunofluorescence intensity of insulin, fewer transferase-mediated dUTP-biotin 3' nick end-labeling (TUNEL)-positive beta cells and higher postprandial GLP-1 and PYY levels than in the Sham group. The improvement in glucose tolerance was reversed at 12 wk postoperatively. Compared with the SG-LFD and DJB-LFD groups, the SG-HFD and DJB-HFD groups showed higher HOMA-IR, down-regulated hepatic and muscular insulin signaling, and more TUNEL-positive beta cells. No significant difference was detected between HFD and LFD groups for body weight, glucose-stimulated insulin secretion, beta-cell mass, immunofluorescence intensity of insulin, and postprandial GLP-1 and PYY levels. Fasting serum ghrelin decreased in SG groups, and there was no difference between HFD-SG and LFD-SG groups. CONCLUSION: HFD reverses the improvement in glucose homeostasis after SG and DJB. Diabetes recurrence may correlate with re-impaired insulin sensitivity, but not with alterations of beta-cell function and body weight.
Asunto(s)
Cirugía Bariátrica , Diabetes Mellitus Experimental/fisiopatología , Células Secretoras de Insulina/citología , Insulina/metabolismo , Animales , Apoptosis , Peso Corporal , Dieta Alta en Grasa , Duodeno/cirugía , Gastrectomía , Ghrelina/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Homeostasis , Resistencia a la Insulina , Yeyuno/cirugía , Hígado/metabolismo , Músculos/metabolismo , Péptido YY/metabolismo , Ratas , Recurrencia , Inducción de Remisión , Transducción de Señal , EstreptozocinaRESUMEN
Low shear stress (LSS) contributes to the pathogenesis of inflammatory diseases, such as atherosclerosis. Notch1 is a type I transmembrane receptor that critically determines the growth, differentiation, and survival of various cell types, but its role and mechanism in LSS-induced inflammatory response remains undetermined. Apolipoprotein E-deficient (ApoE(-/-)) mice were fed with high fat diet and administered intraperitoneally with DAPT (a γ-secretase inhibitor). Perivascular shear stress modifiers were placed around the right carotid arteries to induce LSS. The left carotid arteries with undisturbed shear stress (USS) were used as the control. LSS increased Delta-like 1 (DLL-1) protein expression and the expression of Notch1 and NICD, while DAPT administration reduced NICD expression. Compared with the LSS group, DAPT reduced LSS-induced plaque formation and intercellular adhesion molecule 1 (ICAM-1) expression. Human umbilical vein endothelial cells (HUVECs) were exposure to undisturbed shear stress (USS, 1Pa) or LSS (0.4Pa). Notch1 was inhibited by siRNA or DAPT. RT-PCR and western blotting analysis showed that LSS upregulated the expression of Notch1 in a time-dependent manner. Caveolin-1 (CAV1) inhibition by siRNA could reduce Notch1 and NICD expression. Compared with USS, LSS increased inflammatory response, including IL-1ß and IL-6 secretion, ICAM-1 and inducible nitric oxide synthase (iNOS) expression, and THP-1 cells adhesion. Notch1 inhibition by siRNA or DAPT could reduce these inflammatory responses by reduction of NF-κB phosphorylation, upregulation of IkBα expression, and inhibition of nuclear translocation of NF-κB, while Notch1 activation by DLL-4 had an adverse effect. The Notch signaling system is therefore a potential target for modulating LSS-induced inflammation response during atherosclerosis.