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It remains unclear how hepatic steatosis links to inflammation. Leukocyte cell-derived chemotaxin 2 (LECT2) is a hepatokine that senses fat in the liver and is upregulated prior to weight gain. The aim of this study was to investigate the significance of LECT2 in the development of nonalcoholic steatohepatitis (NASH). In human liver biopsy samples, elevated LECT2 mRNA levels were positively correlated with body mass index (BMI) and increased in patients who have steatosis and inflammation in the liver. LECT2 mRNA levels were also positively correlated with the mRNA levels of the inflammatory genes CCR2 and TLR4 . In C57BL/6J mice fed with a high-fat diet, mRNA levels of the inflammatory cytokines Tnfa and Nos2 were significantly lower in Lect2 KO mice. In flow cytometry analyses, the number of M1-like macrophages and M1/M2 ratio were significantly lower in Lect2 KO mice than in WT mice. In KUP5, mouse kupffer cell line , LECT2 selectively enhanced the LPS-induced phosphorylation of JNK, but not that of ERK and p38. Consistently, LECT2 enhanced the LPS-induced phosphorylation of MKK4 and TAB2, upstream activators of JNK. Hepatic expression of LECT2 is upregulated in association with the inflammatory signature in human liver tissues. The elevation of LECT2 shifts liver residual macrophage to the M1-like phenotype, and contributes to the development of liver inflammation. These findings shed light on the hepatokine LECT2 as a potential therapeutic target that can dissociate liver steatosis from inflammation.

Selenoprotein P is released from the liver and acts through LRP1 in the muscle to contribute to exercise resistance in mouse and man by inhibiting ROS levels via inhibition of AMPK and PGC-1α. Exercise has numerous health-promoting effects in humans 1 ; however, individual responsiveness to exercise with regard to endurance or metabolic health differs markedly 2 , 3 , 4 . This 'exercise resistance' is considered to be congenital, with no evident acquired causative factors. Here we show that the anti-oxidative hepatokine selenoprotein P (SeP) 5 , 6 , 7 causes exercise resistance through its muscle receptor low-density lipoprotein receptor–related protein 1 (LRP1) 8 . SeP-deficient mice showed a 'super-endurance' phenotype after exercise training, as well as enhanced reactive oxygen species (ROS) production, AMP-activated protein kinase (AMPK) phosphorylation 9 and peroxisome proliferative activated receptor γ coactivator (Ppargc)-1α (also known as PGC-1α; encoded by Ppargc1a ) 10 expression in skeletal muscle. Supplementation with the anti-oxidant N -acetylcysteine (NAC) reduced ROS production and the endurance capacity in SeP-deficient mice. SeP treatment impaired hydrogen-peroxide-induced adaptations through LRP1 in cultured myotubes and suppressed exercise-induced AMPK phosphorylation and Ppargc1a gene expression in mouse skeletal muscle—effects which were blunted in mice with a muscle-specific LRP1 deficiency. Furthermore, we found that increased amounts of circulating SeP predicted the ineffectiveness of training on endurance capacity in humans. Our study suggests that inhibitors of the SeP–LRP1 axis may function as exercise-enhancing drugs to treat diseases associated with a sedentary lifestyle.

The liver plays a major role in whole-body energy homeostasis by releasing secretory factors, termed hepatokines. To identify novel target genes associated with insulin resistance, we performed a comprehensive analysis of gene expression profiles using a DNA chip method in liver biopsy samples from humans with varying degrees of insulin resistance. Inhibin βE (INHBE) was identified as a novel putative hepatokine with hepatic gene expression that positively correlated with insulin resistance and body mass index in humans. Quantitative real time-PCR analysis also showed an increase in INHBE gene expression in independent liver samples from insulin-resistant human subjects. Additionally, Inhbe gene expression increased in the livers of db/db mice, a rodent model of type 2 diabetes. To preliminarily screen the role of Inhbe in vivo in whole-body energy metabolic status, hepatic mRNA was knocked down with siRNA for Inhbe (siINHBE) in db/db mice. Treatment with siINHBE suppressed body weight gain during the two-week experimental period, which was attributable to diminished fat rather than lean mass. Additionally, treatment with siINHBE decreased the respiratory quotient and increased plasma total ketone bodies compared with treatment with non-targeting siRNA, both of which suggest enhanced whole-body fat utilization. Our study suggests that INHBE functions as a possible hepatokine to alter the whole-body metabolic status under obese insulin-resistant conditions.

Aim Computer-aided diagnosis (CAD) software for bone scintigrams have recently been introduced as a clinical quality assurance tool. The purpose of this study was to compare the diagnostic accuracy of two CAD systems, one based on a European and one on a Japanese training database, in a group of bone scans from Japanese patients. Method The two CAD software are trained to interpret bone scans using training databases consisting of bone scans with the desired interpretation, metastatic disease or not. One software was trained using 795 bone scans from European patients and the other with 904 bone scans from Japanese patients. The two CAD softwares were evaluated using the same group of 257 Japanese patients, who underwent bone scintigraphy because of suspected metastases of malignant tumors in 2009. The final diagnostic results made by clinicians were used as gold standard. Results The Japanese CAD software showed a higher specificity and accuracy compared to the European CAD software [81 vs. 57 % ( p  < 0.05) and 82 vs. 61 % ( p  < 0.05), respectively]. The sensitivity was 90 % for the Japanese CAD software and 83 % for the European CAD software (n.s). Conclusion The CAD software trained with a Japanese database showed significantly higher performance than the corresponding CAD software trained with a European database for the analysis of bone scans from Japanese patients. These results could at least partly be caused by the physical differences between Japanese and European patients resulting in less influence of attenuation in Japanese patients and possible different judgement of count intensities of hot spots.

Chronic endoplasmic reticulum (ER) stress is a major contributor to obesity-induced insulin resistance in the liver. However, the molecular link between obesity and ER stress remains to be identified. Proteasomes are important multicatalytic enzyme complexes that degrade misfolded and oxidized proteins. Here, we report that both mouse models of obesity and diabetes and proteasome activator (PA)28-null mice showed 30–40% reduction in proteasome activity and accumulation of polyubiquitinated proteins in the liver. PA28-null mice also showed hepatic steatosis, decreased hepatic insulin signaling, and increased hepatic glucose production. The link between proteasome dysfunction and hepatic insulin resistance involves ER stress leading to hyperactivation of c-Jun NH2-terminal kinase in the liver. Administration of a chemical chaperone, phenylbutyric acid (PBA), partially rescued the phenotypes of PA28-null mice. To confirm part of the results obtained from in vivo experiments, we pretreated rat hepatoma-derived H4IIEC3 cells with bortezomib, a selective inhibitor of the 26S proteasome. Bortezomib causes ER stress and insulin resistance in vitro—responses that are partly blocked by PBA. Taken together, our data suggest that proteasome dysfunction mediates obesity-induced ER stress, leading to insulin resistance in the liver.

Mechanical strength improvement on Nb 3 Sn wire is the most important research subject to realize high field magnet applications operated under higher electromagnetic force environment. Recently, we approached to the internal matrix reinforcement technique due to the solid solution mechanism using ternary bronze alloy matrix on the bronze processed Nb3Sn wire. In this study, the effect of the solute element on the mechanical property of the matrix after Nb 3 Sn synthesis heat treatment was evaluated. Several Cu based binary alloys were casted, and these alloys were sintered in order to demonstrate the matrix after Nb 3 Sn synthesis. We confirmed that the both 0.2% proof stress and ultimate tensile stress of the Cu-In alloy was higher than those of the pure Cu and Cu-Zn alloy. The mechanical strength improvement due to the internal matrix reinforcement using Cu-Sn-In ternary alloy matrix was caused by (Cu, In) solid solution formation. The comparisons of mechanical property between several Cu alloys were also investigated for the further mechanical strength improvement.

Leukocyte cell-derived chemotaxin 2 (LECT2) is a hepatokine that causes skeletal muscle insulin resistance. The circulating levels of LECT2 are a possible biomarker that can predict weight cycling because they reflect liver fat and precede the onset of weight loss or gain. Herein, to clarify the dynamics of this rapid change in serum LECT2 levels, we investigated the in vivo kinetics of LECT2, including its plasma half-life and tissue distribution, by injecting 125 I-labelled LECT2 into ICR mice and radioactivity tracing. The injected LECT2 was eliminated from the bloodstream within 10 min (approximate half-life, 5 min). In the kidneys, the radioactivity accumulated within 10 min after injection and declined thereafter. Conversely, the radioactivity in urine increased after 30 min of injection, indicating that LECT2 is mainly excreted by the kidneys into the urine. Finally, LECT2 accumulated in the skeletal muscle and liver until 30 min and 2 min after injection, respectively. LECT2 accumulation was not observed in the adipose tissue. These findings are in agreement with LECT2 action on the skeletal muscle. The present study indicates that LECT2 is a rapid-turnover protein, which renders the circulating level of LECT2 a useful rapid-response biomarker to predict body weight alterations.

The structural basis for the photochromism in the fluorescent protein Dronpa is poorly understood, because the crystal structures of the bright state of the protein did not provide an answer to the mechanism of the photochromism, and structural determination of the dark state has been elusive. We performed NMR analyses of Dronpa in solution at ambient temperatures to find structural flexibility of the protein in the dark state. Light-induced changes in interactions between the chromophore and β-barrel are responsible for switching between the two states. In the bright state, the apex of the chromophore tethers to the barrel by a hydrogen bond, and an imidazole ring protruding from the barrel stabilizes the plane of the chromophore. These interactions are disrupted by strong illumination with blue light, and the chromophore, together with a part of the β-barrel, becomes flexible, leading to a nonradiative decay process.

In that model, mitochondrial β oxidation‐derived reactive oxygen species (ROS) play a causal role in the palmitate‐induced c‐Jun NH2‐terminal kinase activation . [...]toxic lipid‐induced mitochondrial ROS might underlie the link between steatosis and insulin resistance in the liver. [...]NEFA overload is considered sufficient to increase ex vivo hepatic oxidative metabolism, anaplerosis and gluconeogenesis. Pck1 knockdown reduced the hepatic mitochondrial and cytosolic nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide ratio estimated from the plasma acetoacetate/β‐hydroxybutylate and liver lactate/pyruvate ratio, respectively. Because nicotinamide adenine dinucleotide serves as a coenzyme for dehydrogenases in the TCA cycle, a reduced nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide ratio suppresses TCA flux. [...]Satapati et al. examined the significance of oxidative metabolism in human NAFLD pathology.