Activation of Aryl hydrocarbon receptor (AhR) is involved in the control of intestinal mucosal homeostasis. Intestinal barrier dysfunction contributes to the development of many intestinal diseases, such as inflammatory bowel disease (IBD). In this study, we investigated the mechanisms of AhR activation in the maintenance of intestinal barrier function. Adult C57BL/6 mice were treated with dextran sulphate sodium (DSS) for 7 days, with or without 6-Formylindolo(3,2-b)carbazole (FICZ), a ligand of AhR. We found that AhR activation by FICZ attenuated the decreased TJ protein expression in the colonic mucosa of the DSS-induced mice. Further, the increase of both MLC phosphorylation and MLCK expression in the mice with DSS-induced colitis was also significantly inhibited by FICZ induced AhR activation. For in vitro experiments, Caco-2 cells were treated with tumour necrosis factor alpha (TNF-α)/interferon gamma (IFN-γ) for 48 h, with or without FICZ. AhR activation prevented TNF-α/IFN-γ-induced decrease in TER and morphological disruption of the TJs in Caco-2 monolayers. It also inhibited TNF-α/IFN-γ-induced increase in MLCK expression and MLC phosphorylation by suppression of NF-κB p65 signaling pathway. Thus, AhR-activating factors might have potential as therapeutic agents for the treatment of patients with IBD.

Reverse cholesterol transport (RCT) is an antiatherogenic process in which excessive cholesterol from peripheral tissues is transported to the liver and finally excreted from the body via the bile. The nuclear receptor liver receptor homolog 1 (LRH-1) drives expression of genes regulating RCT, and its activity can be modified by different posttranslational modifications. Here, we show that atherosclerosis-prone mice carrying a mutation that abolishes SUMOylation of LRH-1 on K289R develop less aortic plaques than control littermates when exposed to a high-cholesterol diet. The mechanism underlying this atheroprotection involves an increase in RCT and its associated hepatic genes and is secondary to a compromised interaction of LRH-1 K289R with the corepressor prospero homeobox protein 1 (PROX1). Our study reveals that the SUMOylation status of a single nuclear receptor lysine residue can impact the development of a complex metabolic disease such as atherosclerosis.

Various tumors develop addiction to glutamine to support uncontrolled cell proliferation. Here we identify the nuclear receptor liver receptor homolog 1 (LRH-1) as a key regulator in the process of hepatic tumorigenesis through the coordination of a noncanonical glutamine pathway that is reliant on the mitochondrial and cytosolic transaminases glutamate pyruvate transaminase 2 (GPT2) and glutamate oxaloacetate transaminase 1 (GOT1), which fuel anabolic metabolism. In particular, we show that gain and loss of function of hepatic LRH-1 modulate the expression and activity of mitochondrial glutaminase 2 (GLS2), the first and rate-limiting step of this pathway. Acute and chronic deletion of hepatic LRH-1 blunts the deamination of glutamine and reduces glutamine-dependent anaplerosis. The robust reduction in glutaminolysis and the limiting availability of α-ketoglutarate in turn inhibit mTORC1 signaling to eventually block cell growth and proliferation. Collectively, these studies highlight the importance of LRH-1 in coordinating glutamineinduced metabolism and signaling to promote hepatocellular carcinogenesis.Supplemental material is available for this article.Received January 7, 2016; revised version accepted May 12, 2016.During tumorigenesis, cancer cells usually switch from oxidative metabolism to a highly glycolytic metabolic status (Vander Heiden et al. 2009). While glucose is predominantly metabolized into lactate rather than entering the tricarboxylic acid (TCA) cycle, cancer cells particularly rely on glutamine to replenish TCA cycle intermediates. This process, termed anaplerosis, is accomplished through the conversion of glutamine to α-ketoglutarate (α-KG) via a two-step deamination reaction catalyzed by glutaminases and then by glutamate dehydrogenase 1 (GLUD1) or transaminases Wise et al. 2008;Csibi et al. 2013;Son et al. 2013). Cancer cells therefore critically depend on glutamine as a fuel for proliferation, and abrogation of glutamine metabolism blocks tumorigenesis, indicating an accessible therapeutic window for cancer treatment (Hensley et al. 2013).Liver receptor homolog 1 (LRH-1; also called NR5A2) is a nuclear receptor that is enriched in enterohepatic tissues, where it has diverse molecular and physiological functions (Stein and Schoonjans 2015). LRH-1 has been linked to cell proliferation and cancer development in the intestine (Botrugno et al. 2004;Schoonjans et al. 2005) and pancreas (Petersen et al. 2010;Benod et al. 2011). In the liver, LRH-1 regulates various metabolic processes, including bile acid synthesis (Mataki et al. 2007;Lee et al. 2008;Out et al. 2011), glucose sensing and processing (Oosterveer et al. 2012), and reverse cholesterol transport (Stein et al. 2014). Although the function of LRH-1 in the liver has been extensively studied, its commanding role in intermediary metabolism has never been connected to tumorigenesis.In this study, we report that LRH-1 promotes diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) by coordinating glutamine-induced anabolic metabo...

BackgroundCurrently, many clinical trials have shown that inulin-type fructans (ITF) supplementation is associated with glycemic control; nevertheless, the results are inconclusive. The aim of this meta-analysis of randomized controlled trials was to assess the effects of ITF supplementation on glycemic control.MethodsPubMed, EMBASE and the Cochrane Library were searched for eligible articles up to March 6, 2019. A random-effects model was used to analyze the pooled results, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was applied to assess the quality of evidence. The dose–response model was used to recommend the daily dose and duration for ITF supplementation.ResultsThirty-three trials involving 1346 participants were included. Overall, ITF supplementation could significantly reduce concentrations of fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), fasting insulin (FINS) and homeostasis model assessment-insulin resistance (HOMA-IR). In the prediabetes and type 2 diabetes (T2DM) population, a more significant reduction in FBG [weighted mean difference (WMD): − 0.60 mmol/l; 95% CI − 0.71, − 0.48 mmol/l; high rate], HbA1c (WMD: − 0.58%; 95% CI − 0.83, − 0.32%; high rate), FINS (WMD: − 1.75 µU/ml; 95% CI − 2.87, − 0.63 µU/ml; low rate), and HOMA-IR (WMD: − 0.69; 95% CI − 1.10, − 0.28; low rate) were observed, and ITF supplementation with a daily dose of 10 g for a duration of 6 weeks and longer was recommended. Moreover, subgroup analyses suggested that the effects of glycemic control were significantly influenced by the sex of the subjects and the type and the method of intake of ITF.ConclusionsOur analyses confirmed that these four main glycemic indicators were significantly reduced by ITF supplementation, particularly in the prediabetes and T2DM population. Evidence supports that reasonable administration of ITF supplementation may have potential clinical value as an adjuvant therapy for prediabetes and T2DM management.Trial registration The trial was registered at PROSPERO as CRD42018115875 on November 23, 2018.

SummaryThe development of human erythroid cells has been mostly examined in models of adult hematopoiesis, while their early derivation during embryonic and fetal stages is largely unknown. We observed the development and maturation of erythroblasts derived from human pluripotent stem cells (hPSCs) by an efficient co-culture system. These hPSC-derived early erythroblasts initially showed definitive characteristics with a glycophorin A+ (GPA+) CD34lowCD36− phenotype and were distinct from adult CD34+ cell-derived ones. After losing CD34 expression, early GPA+CD36− erythroblasts matured into GPA+CD36low/+ stage as the latter expressed higher levels of β-globin along with a gradual loss of mesodermal and endothelial properties, and terminally suppressed CD36. We establish a unique in vitro model to trace the early development of hPSC-derived erythroblasts by serial expression of CD34, GPA, and CD36. Our findings may provide insight into the understanding of human early erythropoiesis and, ultimately, therapeutic potential.

Background The gut‐liver axis is considered to play a critical role in the development and progression of nonalcoholic fatty liver disease (NAFLD). The integrity of the epithelial barrier is crucial to protect the liver against the invasion of microbial products from the gut, although its exact role in NAFLD onset and progression is not clear. Methods We performed a systematic review and meta‐analysis of studies that addressed the intestinal permeability (IP) in association with NAFLD presence or severity as defined by the presence of nonalcoholic steatohepatitis (NASH) and the degree of steatosis, hepatic inflammation or fibrosis. A total of 14 studies were eligible for inclusion. Results Studies investigating IP in adult (n = 6) and paediatric (n = 8) NAFLD showed similar results. Thirteen of the included studies focussed on small IP, two studies on whole gut permeability and none on colonic permeability. In the pooled analysis, NAFLD patients showed an increased small intestinal permeability compared to healthy controls based on dual sugar tests (standardized mean difference 0.79, 95% CI 0.49‐1.08) and serum zonulin levels (standardized mean difference 1.04 ng/mL, 95% CI 0.40‐1.68). No clear difference in IP was observed between simple steatosis and NASH patients. Furthermore, whole gut and small intestinal permeability increased with the degree of hepatic steatosis in 4/4 studies, while no association with hepatic inflammation or fibrosis was observed. Conclusion Based on the limited number of studies available, IP appears to be increased in NAFLD patients compared to healthy controls and is associated with the degree of hepatic steatosis.

Summary GATA2 is essential for the endothelial-to-hematopoietic transition (EHT) and generation of hematopoietic stem cells (HSCs). It is poorly understood how GATA2 controls the development of human pluripotent stem cell (hPSC)-derived HS-like cells. Here, using human embryonic stem cells (hESCs) in which GATA2 overexpression was induced by doxycycline (Dox), we elucidated the dual functions of GATA2 in definitive hematopoiesis before and after the emergence of CD34 + CD45 + CD90 + CD38 – HS-like cells. Specifically, GATA2 promoted expansion of hemogenic precursors via the EHT and then helped to maintain HS-like cells in a quiescent state by regulating cell cycle. RNA sequencing showed that hPSC-derived HS-like cells were very similar to human fetal liver-derived HSCs. Our findings will help to elucidate the mechanism that controls the early stages of human definitive hematopoiesis and may help to develop a strategy to generate hPSC-derived HSCs.

Highlights d Cryo-EM structures of the human GluN1-GluN2A NMDA receptor resolved at pH 7.8 and pH 6.3 d The GluN2A-NTD adopts an open-and-twisted conformation in the agonist-bound state d Structures and modeling reveal that proton binding promotes closure of the GluN2A-NTD d Proton-induced NTD rearrangement is allosterically coupled to agonist-binding domains