Transketolase promotes MAFLD by limiting inosine-induced mitochondrial activity.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has a global prevalence of about 25% and no approved therapy. Using metabolomic and proteomic analyses, we identified high expression of hepatic transketolase (TKT), a metabolic enzyme of the pentose phosphate pathway, in human and mouse MAFLD. Hyperinsulinemia promoted TKT expression through the insulin receptor-CCAAT/enhancer-binding protein alpha axis. Utilizing liver-specific TKT overexpression and knockout mouse models, we demonstrated that TKT was sufficient and required for MAFLD progression. Further metabolic flux analysis revealed that Tkt deletion increased hepatic inosine levels to activate the protein kinase A-cAMP response element binding protein cascade, promote phosphatidylcholine synthesis, and improve mitochondrial function. Moreover, insulin induced hepatic TKT to limit inosine-dependent mitochondrial activity. Importantly, N-acetylgalactosamine (GalNAc)-siRNA conjugates targeting hepatic TKT showed promising therapeutic effects on mouse MAFLD. Our study uncovers how hyperinsulinemia regulates TKT-orchestrated inosine metabolism and mitochondrial function and provides a novel therapeutic strategy for MAFLD prevention and treatment.

Loss of transketolase promotes the anti-diabetic role of brown adipose tissues.

Transketolase (TKT), an enzyme in the non-oxidative branch of the pentose phosphate pathway (PPP), bi-directionally regulates the carbon flux between the PPP and glycolysis. Loss of TKT in adipose tissues decreased glycolysis and increased lipolysis and uncoupling protein-1 (UCP1) expression, protecting mice from high-fat diet-induced obesity. However, the role of TKT in brown adipose tissue (BAT)-dependent glucose homeostasis under normal chow diet remains to be elucidated. We found that TKT ablation increased levels of glucose transporter 4 (GLUT4), promoting glucose uptake and glycogen accumulation in BAT. Using the streptozotocin (STZ)-induced diabetic mouse model, we discovered that enhanced glucose uptake due to TKT deficiency in BAT contributed to decreasing blood glucose and weight loss, protecting mice from STZ-induced diabetes. Mechanistically, TKT deficiency decreased the level of thioredoxin-interacting protein, a known inhibitor for GLUT4, by decreasing NADPH and glutathione levels and inducing oxidative stress in BAT. Therefore, our data reveal a new role of TKT in regulating the anti-diabetic function of BAT as well as glucose homeostasis.

MEK1-dependent MondoA phosphorylation regulates glucose uptake in response to ketone bodies in colorectal cancer cells.

The Mondo family transcription factor MondoA plays a pivotal role in sensing metabolites, such as glucose, glutamine, and lactic acid, to regulate glucose metabolism and cell proliferation. Ketone bodies are important signals for reducing glucose uptake. However, it is unclear whether MondoA functions in ketone body-regulated glucose transport. Here we reported that ketone bodies promoted MondoA nuclear translocation and binding to the promoter of its target gene TXNIP. Ketone bodies reduced glucose uptake, increased apoptosis and decreased proliferation of colorectal cancer cells, which was impeded by MondoA knockdown. Moreover, we identified MEK1 as a novel component of the MondoA protein complex using a proteomic approach. Mechanistically, MEK1 interacted with MondoA and enhanced tyrosine 222, but not serine or threonine, phosphorylation of MondoA, inhibiting MondoA nuclear translocation and transcriptional activity. Ketone bodies decreased MEK1-dependent MondoA phosphorylation by blocking MondoA and MEK1 interaction, leading to MondoA nuclear translocation, TXNIP transcription, and inhibition of glucose uptake. Therefore, our study not only demonstrated that ketone bodies reduce glucose uptake, promote apoptosis, and inhibit cell proliferation in colorectal cancer cells by regulating MondoA phosphorylation but also identified MEK1-dependent phosphorylation as a new mechanism to manipulate MondoA activity.

High-temperature magnetic skyrmions in BiCrX3 (X = Se and Te) monolayers.

Two-dimensional magnetic van der Waals materials provide a fertile platform for the design and control of topological spin textures such as skyrmions. However, despite studies reporting skyrmions in many 2D magnetic systems, those of the hosting van der Waals materials remain limited. Here, via first-principles calculations and Monte Carlo simulations, we propose BiCrX3 as a new family of materials for hosting skyrmions. Due to the large SOC of the X atom and intrinsic inversion asymmetry, an inherent large DMI occurs in all systems, enabling intriguing Néel-type skyrmions. Furthermore, upon applying a moderate magnetic field, isolated skyrmions and skyrmion lattices emerge in our systems, and are robust within a relatively wide temperature range.

Meta-Analysis of the Effects of Cardiac Rehabilitation on Exercise Tolerance and Cardiac Function in Heart Failure Patients Undergoing Cardiac Resynchronization Therapy.

OBJECTIVE: To evaluate the effects of cardiac rehabilitation on exercise tolerance and cardiac function in heart failure patients undergoing cardiac resynchronization therapy (CRT). METHODS: Randomized controlled trials were initially identified from systematic reviews of the literature about cardiac rehabilitation and heart failure patients with CRT. We undertook updated literature searches of the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, CBM, CNKI, and Wanfang databases until July 1, 2017. STATA12.0 software was used. RESULTS: Four randomized controlled studies were included. The total sample size was 157 patients, including 77 in the control group. Cardiac rehabilitation treatment affected the peak VO2 in heart failure patients with CRT (P heterogeneity=0.491, I 2 = 0%). The results lacked heterogeneity, and the data were merged in a fixed-effects model (WMD = 2.17 ml/kg/min, 95% CI (1.42, 2.92), P < 0.001). The peak VO2 was significantly higher in the cardiac rehabilitation group than in the control group. The sensitivity analysis showed that the results of the meta-analysis were robust. Cardiac rehabilitation treatment affected LVEF in heart failure patients with CRT (P heterogeneity=0.064, I 2 = 63.6%); the heterogeneity among the various research results meant that the data were merged in a random-effects model (WMD = 4.75%, 95% CI (1.53, 7.97), P=0.004). The LVEF was significantly higher in the cardiac rehabilitation group than in the control group. The sources of heterogeneity were analyzed, and it was found that one of the studies was the source of significant heterogeneity. After the elimination of that study, the data were reanalyzed, and the heterogeneity was significantly reduced. There were still significant differences in the WMD and 95% CI. CONCLUSION: Cardiac rehabilitation can improve exercise tolerance and cardiac function in heart failure patients with CRT. Future studies are needed to evaluate whether these beneficial effects of cardiac rehabilitation may translate into an improvement in long-term clinical outcomes among these patients.