Ketone bodies promote epididymal white adipose expansion to alleviate liver steatosis in response to a ketogenic diet.

Liver can sense the nutrient status and send signals to other organs to regulate overall metabolic homoeostasis. Herein, we demonstrate that ketone bodies act as signals released from the liver that specifically determine the distribution of excess lipid in epididymal white adipose tissue (eWAT) when exposed to a ketogenic diet (KD). An acute KD can immediately result in excess lipid deposition in the liver. Subsequently, the liver sends the ketone body ß-hydroxybutyrate (BHB) to regulate white adipose expansion, including adipogenesis and lipogenesis, to alleviate hepatic lipid accumulation. When ketone bodies are depleted by deleting 3-hydroxy-3-methylglutaryl-CoA synthase 2 gene in the liver, the enhanced lipid deposition in eWAT but not in inguinal white adipose tissue is preferentially blocked, while lipid accumulation in liver is not alleviated. Mechanistically, ketone body BHB can significantly decrease lysine acetylation of peroxisome proliferator-activated receptor gamma in eWAT, causing enhanced activity of peroxisome proliferator-activated receptor gamma, the key adipogenic transcription factor. These observations suggest that the liver senses metabolic stress first and sends a corresponding signal, that is, ketone body BHB, to specifically promote eWAT expansion to adapt to metabolic challenges.

A handy imaging sensor array based on the phase transformation from CsPbBr3 to CsPb2Br5: highly sensitive and rapid detection of water content in ethanol.

Detection of the water content in ethanol has become very important in many fields; however, well-established methods usually require complex strategies and devices. Herein, a simple and non-instrument methodology was developed for the determination of the water content in ethanol. In this work, a CsPbBr3@PVA imaging array sensor was constructed based on the fluorescence on/off mechanism and applied to the detection of water content for the first time. When preparing CsPbBr3@PVA, the photoluminescence of CsPbBr3 was quenched by water in PVA due to the decomposition of CsPbBr3. By employing ethanol with fast volatilization to remove water, the decomposed composition recrystallized and formed luminescent CsPb2Br5. When the water content in ethanol was increased, the degree of the recovered fluorescence drastically reduced. To develop a portable and easily-operated methodology, the pictures of the sensor array were captured using a smartphone and quickly analyzed with ImageJ to read the gray-level values for each sample. The latter displayed a good linear relationship (R2 = 0.995) with the water content increasing from 0% to 7% in ethanol, and a low limit of detection of 0.006% was achieved. Moreover, the sensor array showed advantages like a fast response speed (5 s), strong selectivity and application potential in real samples. This method does not require expensive spectrometers and professional personnel to operate, having the virtues of low cost, fast detection and high sensitivity.

The unique physical shading pattern of Rayleigh scattering for the generally improved detection of scattering particles.

The Rayleigh scattering method is a rising analytical technique because of its high sensitivity and simple operability in the detection of scattered particles. Herein, an efficient and facile physical shading method (covering the cuvette) based on the Rayleigh scattering pattern was developed, which exhibited overall promotion of sensitivity, linearity, detection limit, precision and accuracy because of its greatly reduced background noise upon measurement even if complicated chemical reagents and instruments were not involved. Protein, as a common scattering particle, is a direct or indirect expression of an organism's state of life. Thus, considering the simple and cost-effective features of the shading treatment, a combination strategy based on the probe was adapted to further enhance the performance of protein detection (the limit of detection (3σ) was reduced by at least 20 times, using Eriochrome Black T as a probe), and the possible reasons for the improvement were deduced theoretically. Furthermore, the technology was successfully applied to detect protein in human urine, giving consistent results. In general, this improvement strategy can be handily integrated into most detection systems based on Rayleigh scattering, and its realization delineates a blueprint for the rapid development of sensors.

An improved dual-channel capacitively coupled contactless conductivity detector with high detection performance.

Conductivity detectors are widely used electrochemical sensors. It has long been a goal of researchers to improve detection performance. In this contribution, we propose a multi-input capacitively coupled contactless conductivity detector (MIC4D) with high sensitivity, and we carry out a detailed theoretical investigation of the detector. In order to overcome the problem of a rising baseline level as a result of sensitivity improvements when using the multi-input detection method, we innovatively combine MIC4D with differential detection to propose a further-improved detector (DFMIC4D). The detector is composed of two channels, one for the reference and the other for the analyte. The signal output from differential amplification can effectively reduce the high baseline level and detection interference. In KCl solution with a concentration range of 10-4 to 10-5 M, the response to the solution is a linear function of the logarithm of the concentration, and this detector has a high slope. The slope of DFMIC4D is 1.393, higher than a traditional single-input capacitively coupled contactless conductivity detector (C4D: 0.905) and a double-input capacitively coupled contactless conductivity detector (DIC4D: 1.314). For 10-3 M KCl solution, the response-to-baseline ratio is 1.776 for C4D, 1.779 for DIC4D, and 12.06 for DFMIC4D, with a ratio increase of nearly 6-fold shown by our new detector. At a S/N (signal-to-noise) ratio of 3, the limit of detection (LOD) of DFMIC4D is low, reaching 0.7 nM. In addition, DFMIC4D can be applied to the detection of low-conductivity solutions and total dissolved solids (TDS) analysis. Compared with a standard conductivity meter, our detector shows better detection performance.

Hepatic Regulator of G Protein Signaling 5 Ameliorates Nonalcoholic Fatty Liver Disease by Suppressing Transforming Growth Factor Beta-Activated Kinase 1-c-Jun-N-Terminal Kinase/p38 Signaling.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, which has no specific pharmacological treatments partially because of the unclear pathophysiological mechanisms. Regulator of G protein signaling (RGSs) proteins are proteins that negatively regulate G protein-coupled receptor (GPCR) signaling. The members of the R4/B subfamily are the smallest RGS proteins in size, and RGS5 belongs to this family, which mediates pluripotent biological functions through canonical G protein-mediated pathways and non-GPCR pathways. This study combined a genetically engineered rodent model and a transcriptomics-sequencing approach to investigate the role and regulatory mechanism of RGS5 in the development of NAFLD. APPROACH AND RESULTS: This study found that RGS5 protects against NAFLD and nonalcoholic steatohepatitis. Using RNA sequencing and an unbiased systematic investigative approach, this study found that the activation of mitogen-activated protein kinase signaling cascades in response to metabolic challenge is negatively associated with hepatic RGS5 expression. Mechanistically, we found that the 64-181 amino-acid-sequence (aa) fragment of RGS5 directly interacts with transforming growth factor beta-activated kinase 1 (TAK1) through the 1-300aa fragment and inhibits TAK1 phosphorylation and the subsequent c-Jun-N-terminal kinase (JNK)/p38 pathway activation. CONCLUSIONS: In hepatocytes, RGS5 is an essential molecule that protects against the progression of NAFLD. RGS5 directly binds to TAK1, preventing its hyperphosphorylation and the activation of the downstream JNK/p38 signaling cascade. RGS5 is a promising target molecule for fine-tuning the activity of TAK1 and for the treatment of NAFLD.

STEAP3 (Six-Transmembrane Epithelial Antigen of Prostate 3) Inhibits Pathological Cardiac Hypertrophy.

Pathological cardiac hypertrophy is one of the major predictors and inducers of heart failure, the end stage of various cardiovascular diseases. However, the molecular mechanisms underlying pathogenesis of pathological cardiac hypertrophy remain largely unknown. Here, we provided the first evidence that STEAP3 (Six-Transmembrane Epithelial Antigen of Prostate 3) is a key negative regulator of this disease. We found that the expression of STEAP3 was reduced in pressure overload-induced hypertrophic hearts and phenylephrine-induced hypertrophic cardiomyocytes. In a transverse aortic constriction-triggered mouse cardiac hypertrophy model, STEAP3 deficiency remarkably deteriorated cardiac hypertrophy and fibrosis, whereas the opposite phenotype was observed in the cardiomyocyte-specific STEAP3 overexpressing mice. Accordingly, STEAP3 significantly mitigated phenylephrine-induced cell enlargement in primary neonatal rat cardiomyocytes. Mechanistically, via RNA-seq and immunoprecipitation-mass screening, we demonstrated that STEAP3 directly bond to Rho family small GTPase 1 and suppressed the activation of downstream mitogen-activated protein kinase-extracellular signal-regulated kinase signaling cascade. Remarkably, the antihypertrophic effect of STEAP3 was largely blocked by overexpression of constitutively active mutant Rac1 (G12V). Our study indicates that STEAP3 serves as a novel negative regulator of pathological cardiac hypertrophy by blocking the activation of the Rac1-dependent signaling cascade and may contribute to exploring effective therapeutic strategies of pathological cardiac hypertrophy treatment.

TNFAIP3 Interacting Protein 3 Overexpression Suppresses Nonalcoholic Steatohepatitis by Blocking TAK1 Activation.

Nonalcoholic steatohepatitis (NASH) is an unmet clinical challenge due to the rapid increase in its occurrence but the lack of approved drugs to treat it. Further unraveling of the molecular mechanisms underlying NASH may identify potential successful drug targets for this condition. Here, we identified TNFAIP3 interacting protein 3 (TNIP3) as a novel inhibitor of NASH. Hepatocyte-specific TNIP3 transgenic overexpression attenuates NASH in two dietary models in mice. Mechanistically, this inhibitory effect of TNIP3 is independent of its conventional role as an inhibitor of TNFAIP3. Rather, TNIP3 directly interacts with TAK1 and inhibits its ubiquitination and activation by the E3 ligase TRIM8 in hepatocytes in response to metabolic stress. Notably, adenovirus-mediated TNIP3 expression in the liver substantially blocks NASH progression in mice. These results suggest that TNIP3 may be a promising therapeutic target for NASH management.