Macrophage CREBZF Orchestrates Inflammatory Response to Potentiate Insulin Resistance and Type 2 Diabetes.

Chronic adipose tissue inflammation accompanied by macrophage accumulation and activation is implicated in the pathogenesis of insulin resistance and type 2 diabetes in humans. The transcriptional coregulator CREBZF is a key factor in hepatic metabolism, yet its role in modulating adipose tissue inflammation and type 2 diabetes remains elusive. The present study demonstrates that overnutrition-induced CREBZF links adipose tissue macrophage (ATM) proinflammatory activation to insulin resistance.

Induced degradation of lineage-specific oncoproteins drives the therapeutic vulnerability of small cell lung cancer to PARP inhibitors.

Although mutations are not commonly found in small cell lung cancer (SCLC), a substantial fraction of SCLC shows clinically relevant response to PARP inhibitors (PARPis). However, the underlying mechanism(s) of PARPi sensitivity in SCLC is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in SCLC cells.

Nimbolide targets RNF114 to induce the trapping of PARP1 and synthetic lethality in -mutated cancer.

Recent studies have pointed to PARP1 trapping as a key determinant of the anticancer effects of PARP1 inhibitors (PARPi). We identified RNF114, as a PARylation-dependent, E3 ubiquitin ligase involved in DNA damage response. Upon sensing genotoxicity, RNF114 was recruited, in a PAR-dependent manner, to DNA lesions, where it targeted PARP1 for degradation.

Time-Frequency Characteristics and Evolution Law of Acoustic Emission Signals during the Deformation and Failure of Deformed Coal.

The research on the time-frequency characteristics and evolution law of acoustic emission (AE) signals during deformed coal failure is more conducive to understand the damage mechanism of coal. In this study, the experiments of AE monitoring during the intact and deformed coal failure were first conducted under loading axial stress and unloading confining stress conditions. Based on the evolution characteristics of volume strain and AE event rate, the damage process of coal was divided into three stages: nonfracture development stage, stable development stage of fracture, and unstable development stage of fracture.

Intrahepatic osteopontin signaling by CREBZF defines a checkpoint for steatosis-to-NASH progression.

Background And Aims: NASH has emerged as a leading cause of chronic liver disease. However, the mechanisms that govern NASH fibrosis remain largely unknown. CREBZF is a CREB/ATF bZIP transcription factor that causes hepatic steatosis and metabolic defects in obesity.

Pulse-Modulation Eddy Current Evaluation of Interlaminar Corrosion in Stratified Conductors: Semi-Analytical Modeling and Experiments.

Interlaminar corrosion (ILC) poses a severe threat to stratified conductors which are broadly employed in engineering fields including aerospace, energy, etc. Therefore, for the pressing concern regarding the safety and integrity of stratified conductors, it is imperative to non-intrusively and quantitatively interrogate ILC via non-destructive evaluation techniques. In this paper, pulse-modulation eddy current (PMEC) for imaging and assessment of ILC is intensively investigated through theoretical simulations and experiments.

Sodium Butyrate Supplementation Inhibits Hepatic Steatosis by Stimulating Liver Kinase B1 and Insulin-Induced Gene.

Background And Aims: Butyric acid is an intestinal microbiota-produced short-chain fatty acid, which exerts salutary effects on alleviating nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism of butyrate on regulating hepatic lipid metabolism is largely unexplored.

Methods: A mouse model of NAFLD was induced with high-fat diet feeding, and sodium butyrate (NaB) intervention was initiated at the eighth week and lasted for 8 weeks.

Activating Adenosine Monophosphate-Activated Protein Kinase Mediates Fibroblast Growth Factor 1 Protection From Nonalcoholic Fatty Liver Disease in Mice.

Background And Aims: Fibroblast growth factor (FGF) 1 demonstrated protection against nonalcoholic fatty liver disease (NAFLD) in type 2 diabetic and obese mice by an uncertain mechanism. This study investigated the therapeutic activity and mechanism of a nonmitogenic FGF1 variant carrying 3 substitutions of heparin-binding sites (FGF1 ) against NAFLD.

Approach And Results: FGF1 administration was effective in 9-month-old diabetic mice carrying a homozygous mutation in the leptin receptor gene (db/db) with NAFLD; liver weight, lipid deposition, and inflammation declined and liver injury decreased.

Thrombospondin 1 improves hepatic steatosis in diet-induced insulin-resistant mice and is associated with hepatic fat content in humans.

Background: Nonalcoholic fatty liver disease (NAFLD) is associated with altered production of secreted proteins. Increased understanding of secreted proteins could lead to improved prediction and treatment of NAFLD. Here, we aimed to discover novel secreted proteins in humans that are associated with hepatic fat content using unbiased proteomic profiling strategy, and how the identified Thbs1 modulates lipid metabolism and hepatic steatosis.

The Effects of B1344, a Novel Fibroblast Growth Factor 21 Analog, on Nonalcoholic Steatohepatitis in Nonhuman Primates.

Nonalcoholic steatohepatitis has emerged as a major cause of liver diseases with no effective therapies. Here, we evaluate the efficacies and pharmacokinetics of B1344, a long-acting polyethylene glycolylated (PEGylated) fibroblast growth factor 21 analog, in a nongenetically modified nonhuman primate species that underwent liver biopsy and demonstrate the potential for efficacies in humans. B1344 is sufficient to selectively activate signaling from the βKlotho/FGFR1c receptor complex.

Characteristics Regarding Lift-Off Intersection of Pulse-Modulation Eddy Current Signals for Evaluation of Hidden Thickness Loss in Cladded Conductors.

The cladded conductor is broadly utilized in engineering fields, such as aerospace, energy, and petrochemical; however, it is vulnerable to thickness loss occurring in the clad layer and nonconductive protection coating due to abrasive and corrosive environments. Such a flaw severely undermines the integrity and safety of the mechanical structures. Therefore, evaluating the thickness loss hidden inside cladded conductors via reliable nondestructive evaluation techniques is imperative.

Indole-3-propionic acid inhibits gut dysbiosis and endotoxin leakage to attenuate steatohepatitis in rats.

Microbial metabolites have emerged as critical components that mediate the metabolic effects of the gut microbiota. Here, we show that indole-3-propionic acid (IPA), a tryptophan metabolite produced by gut bacteria, is a potent anti-non-alcoholic steatohepatitis (NASH) microbial metabolite. Here, we demonstrate that administration of IPA modulates the microbiota composition in the gut and inhibits microbial dysbiosis in rats fed a high-fat diet.

CREBZF as a Key Regulator of STAT3 Pathway in the Control of Liver Regeneration in Mice.

Background And Aims: STAT3, a member of the signal transducer and activator of transcription (STAT) family, is strongly associated with liver injury, inflammation, regeneration, and hepatocellular carcinoma development. However, the signals that regulate STAT3 activity are not completely understood.

Approach And Results: Here we characterize CREB/ATF bZIP transcription factor CREBZF as a critical regulator of STAT3 in the hepatocyte to repress liver regeneration.

Post-translational regulation of lipogenesis via AMPK-dependent phosphorylation of insulin-induced gene.

Insulin-induced gene (Insig) negatively regulates SREBP-mediated de novo fatty acid synthesis in the liver. However, the upstream regulation of Insig is incompletely understood. Here we report that AMPK interacts with and mediates phosphorylation of Insig.

The Circadian Protein Period2 Suppresses mTORC1 Activity via Recruiting Tsc1 to mTORC1 Complex.

Although emerging evidence indicates an important role of the circadian clock in modulating the diurnal oscillation of mammalian target of rapamycin complex 1 (mTORC1) signaling, the underlying molecular mechanism remains elusive. Here we show that Period2 (Per2), a core clock protein, functions as a scaffold protein to tether tuberous sclerosis complex 1 (Tsc1), Raptor, and mTOR together to specifically suppress the activity of mTORC1 complex. Due to the loss of its inhibition of mTORC1, Per2 deficiency significantly enhances protein synthesis and cell proliferation but reduces autophagy.

The ER-localized Ca-binding protein calreticulin couples ER stress to autophagy by associating with microtubule-associated protein 1A/1B light chain 3.

Autophagy is of key importance for eliminating aggregated proteins during the maintenance of cellular proteostasis in response to endoplasmic reticulum (ER) stress. However, the upstream signaling that mediates autophagy activation in response to ER stress is incompletely understood. In this study, and approaches were utilized that include gain- and loss-of-function assays and mouse livers and human cell lines with tunicamycin-induced pharmacological ER stress.

Berberine attenuates hepatic steatosis and enhances energy expenditure in mice by inducing autophagy and fibroblast growth factor 21.

Background And Purpose: Berberine, a compound from rhizome coptidis, is traditionally used to treat gastrointestinal infections, such as bacterial diarrhoea. Recently, berberine was shown to have hypoglycaemic and hypolipidaemic effects. We investigated the mechanisms by which berberine regulates hepatic lipid metabolism and energy expenditure in mice.

Hepatic ATF6 Increases Fatty Acid Oxidation to Attenuate Hepatic Steatosis in Mice Through Peroxisome Proliferator-Activated Receptor α.

The endoplasmic reticulum quality control protein activating transcription factor 6 (ATF6) has emerged as a novel metabolic regulator. Here, we show that adenovirus-mediated overexpression of the dominant-negative form of ATF6 (dnATF6) increases susceptibility to develop hepatic steatosis in diet-induced insulin-resistant mice and fasted mice. Overexpression of dnATF6 or small interfering RNA-mediated knockdown of ATF6 decreases the transcriptional activity of peroxisome proliferator-activated receptor α (PPARα)/retinoid X receptor complex, and inhibits oxygen consumption rates in hepatocytes, possibly through inhibition of the binding of PPARα to the promoter of its target gene.