RESUMEN
Previous studies have shown that reduced levels of the adipocyte fatty acid binding protein (FABP)4 (AFABP/aP2), result in metabolic improvement including potentiated insulin sensitivity and attenuated atherosclerosis. Mechanistically, pharmacologic or genetic inhibition of FABP4 in macrophages upregulates UCP2, attenuates reactive oxygen species (ROS) production, polarizes cells toward the anti-inflammatory M2 state, and reduces leukotriene (LT) secretion. At the protein level, FABP4 stabilizes LTA4 toward chemical hydrolysis, thereby potentiating inflammatory LTC4 synthesis. Herein, we extend the FABP4-LT axis and demonstrate that genetic knockout of FABP4 reduces expression of the major macrophage LT receptor, LTB4 receptor 1 (BLT1R), via a ROS-dependent mechanism. Consistent with inflammation driving BLT1R expression, M1 polarized macrophages express increased levels of BLT1R relative to M2 polarized macrophages and treatment with proinflammatory lipopolysaccharide increased BLT1R mRNA and protein expression. In FABP4 knockout macrophages, silencing of UCP2, increased ROS levels and led to increased expression of BLT1R mRNA. Similarly, addition of exogenous H2O2 upregulated BLT1R expression, whereas the addition of a ROS scavenger, N-acetyl cysteine, decreased BLT1R levels. As compared with WT macrophages, LTB4-BLT1R-dependent JAK2-phosphorylation was reduced in FABP4 knockout macrophages. In summary, these results indicate that FABP4 regulates the expression of BLT1R and its downstream signaling via control of oxidative stress in macrophages.
Asunto(s)
Proteínas de Unión a Ácidos Grasos/metabolismo , Receptores de Leucotrieno B4/genética , Transducción de Señal , Animales , Regulación de la Expresión Génica , Técnicas de Inactivación de Genes , Lipopolisacáridos/farmacología , Ratones , Células RAW 264.7 , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteína Desacopladora 2/metabolismoRESUMEN
OBJECTIVES: To measure changes in the composition of serum bile acids (BA) and the expression of Takeda G-protein-coupled receptor 5 (TGR5) acutely after bariatric surgery or caloric restriction. SUMMARY BACKGROUND DATA: Metabolic improvement after bariatric surgery occurs before substantial weight loss. BA are important metabolic regulators acting through the farnesoid X receptor and TGR5 receptor. The acute effects of surgery on BA and the TGR5 receptor in subcutaneous white adipose tissue (WAT) are unknown. METHODS: A total of 27 obese patients with type 2 diabetes mellitus were randomized to Roux-en-Y gastric bypass (RYGB) or to hypocaloric diet (HC diet) restriction (NCT 1882036). A cohort of obese patients with and without type 2 diabetes mellitus undergoing vertical sleeve gastrectomy was also recruited (n = 12) as a comparison. RESULTS: After vertical sleeve gastrectomy, the level of BA increased [total: 1.17â±â1.56âµmol/L to 4.42â±â3.92âµmol/L (P = 0.005); conjugated BA levels increased from 0.99â±â1.42âµmol/L to 3.59â±â3.70âµmol/L (P = 0.01) and unconjugated BA levels increased from 0.18â±â0.24âµmol/L to 0.83â±â0.70âµmol/L (P = 0.009)]. With RYGB, there was a trend toward increased BA [total: 1.37â±â0.97âµmol/L to 3.26â±â3.01âµmol/L (P = 0.07); conjugated: 1.06â±â0.81âµmol/L to 2.99â±â3.02âµmol/L (P = 0.06)]. After HC diet, the level of unconjugated BA decreased [0.92â±â0.55âµmol/L to 0.32 ± 0.43âµmol/L (P = 0.05)]. The level of WAT TGR5 gene expression decreased after surgery, but not in HC diet. Protein levels did not change. CONCLUSIONS: The levels of serum BA increase after bariatric surgery independently from caloric restriction, whereas the level of WAT TGR5 protein is unaffected.