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The article discusses the discovery of a selective cytochrome P450 4A inhibitor for the treatment of Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD). The study identifies CYP4A inhibitors that effectively reduce hepatic steatosis and improve metabolic abnormalities associated with MAFLD in both in vitro and in vivo models. The inhibitors operate through mechanisms targeting ER stress/oxidative stress, Fatty acid translocase (FAT/CD36)/lipotoxicity, and inflammation/fibrosis, showing promising therapeutic potential for MAFLD treatment. The research was conducted by a team of authors who have declared no conflict of interest and was supported by grants from the Korea Basic Science Institute and the National Research Foundation of Korea. [Extracted from the article]

Introduction Skeletal muscle is a major contributor to systemic energy homeostasis because of its large mass relative to other tissues and its high rate of fuel consumption. Mammalian skeletal muscles [...], Skeletal muscle is a key organ in energy homeostasis owing to its high requirement for nutrients. Heterotrimeric G proteins converge signals from cell-surface receptors to potentiate or blunt responses against environmental changes. Here, we show that muscle-specific ablation of G[alpha]13 in mice promotes reprogramming of myofibers to the oxidative type, with resultant increases in mitochondrial biogenesis and cellular respiration. Mechanistically, G[alpha]13 and its downstream effector RhoA suppressed nuclear factor of activated T cells 1 (NFATc1), a chief regulator of myofiber conversion, by increasing Rho-associated kinase 2-mediated (Rock2-mediated) phosphorylation at Ser243. Ser243 phosphorylation of NFATc1 was reduced after exercise, but was higher in obese animals. Consequently, G[alpha]13 ablation in muscles enhanced whole-body energy metabolism and increased insulin sensitivity, thus affording protection from diet-induced obesity and hepatic steatosis. Our results define G[alpha]13 as a switch regulator of myofiber reprogramming, implying that modulations of G[alpha]13 and its downstream effectors in skeletal muscle are a potential therapeutic approach to treating metabolic diseases.

Targeting ITIH1 in metabolic disease: The liver releases secretory proteins in response to metabolic stress. Kim et al. report a decrease in Gα13 in the liver of mice and humans with diabetes. Secretome analysis enabled identification of a specific protein (ITIH1) highly secreted by liver in association with insulin resistance and consequent hyperglycemia. Glycosyl modification of ITIH1 facilitated its deposition on the hyaluronan surrounding mouse adipose tissue and skeletal muscle, making a physical barrier between insulin and its receptor. Neutralization of secreted ITIH1 prevented systemic insulin resistance and ameliorated glucose intolerance in mice. This finding may contribute to developing a new strategy to treat metabolic diseases. The impact of liver disease on whole-body glucose homeostasis is largely attributed to dysregulated release of secretory proteins in response to metabolic stress. The molecular cues linking liver to whole-body glucose metabolism remain elusive. We found that expression of G protein α-13 (Gα13) was decreased in the liver of mice and humans with diabetes. Liver-specific deletion of the Gna13 gene in mice resulted in systemic glucose intolerance. Comparative secretome analysis identified inter-α-trypsin inhibitor heavy chain 1 (ITIH1) as a protein secreted by liver that was responsible for systemic insulin resistance in Gna13-deficient mice. Liver expression of ITIH1 positively correlated with surrogate markers for diabetes in patients with impaired glucose tolerance or overt diabetes. Mechanistically, a decrease in hepatic Gα13 caused ITIH1 oversecretion by liver through induction of O-GlcNAc transferase expression, facilitating ITIH1 deposition on the hyaluronan surrounding mouse adipose tissue and skeletal muscle. Neutralization of secreted ITIH1 ameliorated glucose intolerance in obese mice. Our findings demonstrate systemic insulin resistance in mice resulting from liver-secreted ITIH1 downstream of Gα13 and its reversal by ITIH1 neutralization. [ABSTRACT FROM AUTHOR]

Adipose tissues considerably influence metabolic homeostasis, and both white (WAT) and brown (BAT) adipose tissue play significant roles in lipid and glucose metabolism. O-linked N-acetylglucosamine (O-GlcNAc) modification is characterized by the addition of N-acetylglucosamine to various proteins by O-GlcNAc transferase (Ogt), subsequently modulating various cellular processes. However, little is known about the role of O-GlcNAc modification in adipose tissues. Here, we report the critical role of O-GlcNAc modification in cold-induced thermogenesis. Deletion of Ogt in WAT and BAT using adiponectin promoter-driven Cre recombinase resulted in severe cold intolerance with decreased uncoupling protein 1 (Ucp1) expression. Furthermore, Ogt deletion led to decreased mitochondrial protein expression in conjunction with decreased peroxisome proliferator-activated receptor γ coactivator 1-α protein expression. This phenotype was further confirmed by deletion of Ogt in BAT using Ucp1 promoter-driven Cre recombinase, suggesting that O-GlcNAc modification in BAT is responsible for cold-induced thermogenesis. Hypothermia was significant under fasting conditions. This effect was mitigated after normal diet consumption but not after consumption of a fatty acid-rich ketogenic diet lacking carbohydrates, suggesting impaired diet-induced thermogenesis, particularly by fat. In conclusion, O-GlcNAc modification is essential for cold-induced thermogenesis and mitochondrial biogenesis in BAT. Glucose flux into BAT may be a signal to maintain BAT physiological responses. [ABSTRACT FROM AUTHOR]

An osmosensing mechanism of Saccharomyces cerevisiae involves a mitogen-activated protein kinase (MAPK) cascade (HOG pathway). This study aimed to investigate the response of the yeast to osmotic stress. A mutant strain, in which the HOG1 gene was disrupted by TRP1, was constructed. A spontaneous mutant, named YJY45, which suppresses the osmosensitive growth phenotype of the hog1 deletion mutant, was selected and showed a secondary phenotype of temperature sensitivity on YPD containing 0.5 M NaCl at 37°C. Our data indicate that the spontaneous mutation in YJY45 mutant was mapped in KSS1, which is one of the MAPK family. The mutation in KSS1 suppresses the osmolarity-hypersensitive phenotype of the hog1 deletion mutation and restores GPD1 induction. [Copyright &y& Elsevier]

This corrects the article DOI: 10.1038/ncomms14477 [ABSTRACT FROM AUTHOR]

Cancer cells usually obtain energy from a high rate of glycolysis rather than oxidative phosphorylation under normoxia as well as hypoxia. Under these circumstances, pyruvate, the end-product of glycolysis, accumulates in cancer cells. We have previously reported that pyruvate activates endothelial cells and induces angiogenesis. Here, we examined the angiogenic activity of pyruvate in tumor cells. Plasminogen activator inhibitor-1 (PAI-1), the gene most upregulated by pyruvate, showed a pro-angiogenic activity, which was abolished by a PAI-1 neutralizing antibody. Moreover, stabilization of hypoxia-inducible factor-1α (HIF-1α) by pyruvate was required for induction of PAI-1 transcription through direct binding to hypoxia response element-2 (HRE-2) on the promoter. These results suggest that pyruvate can activate the angiogenic activity of cancer cells under normoxia and that PAI-1 may act as a pro-angiogenic factor in pyruvate-induced angiogenesis.

Angiogenesis is important in the development and progression of cancer, therefore the therapeutic approach based on anti-angiogenesis may represent a promising therapeutic option. KR-31831 is a novel anti-ischemic agent. Previously, we reported the anti-angiogenic activity of KR-31831. In the present study we investigated the molecular mechanisms underlying anti-angiogenic activity of KR-31831. We show that KR-31831 inhibits vascular endothelial growth factor (VEGF)-induced proliferation and tube formation via release of intracellular Ca2+ and phosphorylation of extra-cellular regulated kinase 1/2 (Erk 1/2) in human umbilical vein endothelial cells (HUVECs). Moreover, the expression of VEGF receptor 2 (VEGFR2, known as Flk-1 or KDR) was reduced by the treatment of KR-31831. These results suggest that KR-31831 may have inhibitory effects on tumor angiogenesis through down-regulation of KDR expression.

Glioblastomas are highly vascularized tumors and anti-angiogenic strategy is one of the most promising therapeutic approaches to treat brain tumors. Interferon alpha (IFN-alpha) as a single agent or combined with standard chemo-therapy has been shown to inhibit various tumors, but the effect of combination anti-angiogenic therapy on brain tumors has not been well studied. We determined the optimal dose and schedule of pegylated IFN-alpha (PEG-IFN-alpha) against U-87MG human glioblastoma cells growing orthotopically in nude mice, since several clinical trials reported that PEG-IFN-alpha administered at higher or lower doses was less effective. The group treated two times per week with injections of 10 KU of PEG-IFN-alpha for 4 weeks showed significant decreases in cell proliferation and angiogenesis. Moreover, the optimal dose and schedule of PEG-IFN-alpha determined in this study and combined with paclitaxel treatment potently inhibited tumor growth in vivo. The mechanisms of the significant therapeutic effects were most likely caused by directly inhibiting cell proliferation and angiogenesis, and rendering apoptosis increased. Specifically PEG-IFN-alpha/paclitaxel combination induced apoptosis of tumor-associated endothelial cells more than that of tumor cells. These results suggest that optimal biological dosage and scheduling of PEG-IFN-alpha and paclitaxel combination is a potent strategy for glioblastoma patients as a new synergistic anti-endothelial treatment.