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Growth hormone (GH) is one of the critical factors in maintaining glucose metabolism. B-cell translocation gene 2 (BTG2) and yin yang 1 (YY1) are key regulators of diverse metabolic processes. In this study, we investigated the link between GH and BTG2–YY1 signaling pathway in glucose metabolism. GH treatment elevated the expression of hepatic Btg2 and Yy1 in primary mouse hepatocytes and mouse livers. Glucose production in primary mouse hepatocytes and serum blood glucose levels were increased during GH exposure. Overexpression of hepatic Btg2 and Yy1 induced key gluconeogenic enzymes phosphoenolpyruvate carboxykinase 1 (PCK1) and glucose-6 phosphatase (G6PC) as well as glucose production in primary mouse hepatocytes, whereas this phenomenon was markedly diminished by knockdown of Btg2 and Yy1. Here, we identified the YY1-binding site on the Pck1 and G6pc gene promoters using reporter assays and point mutation analysis. The regulation of hepatic gluconeogenic genes induced by GH treatment was clearly linked with YY1 recruitment on gluconeogenic gene promoters. Overall, this study demonstrates that BTG2 and YY1 are novel regulators of GH-dependent regulation of hepatic gluconeogenic genes and glucose production. BTG2 and YY1 may be crucial therapeutic targets to intervene in metabolic dysfunction in response to the GH-dependent signaling pathway. [ABSTRACT FROM AUTHOR]

Alcoholic liver disease is the most prevalent chronic liver disease. Melatonin is known to control many vital processes. Here, we explored a novel molecular mechanism by which melatonin‐induced SIRT1 signaling protects against alcohol‐mediated oxidative stress and liver injury. Gene expression profiles and metabolic changes were measured in liver specimens of mice and human subjects. Expression levels of Cb1r, Crbn, Btg2, Yy1, pro‐inflammatory cytokines, and Cyp2e1 were significantly enhanced in chronic alcohol‐challenged mice and human subjects. Levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic CYP2E1 protein, and reactive oxygen species (ROS) were elevated in alcohol‐fed WT mice but not in Cb1r antagonist‐treated, Crbn null, or Yy1‐silenced mice. Importantly, alcohol‐induced Yy1 and Cyp2e1 expression, ROS amount, and liver injury were markedly diminished by melatonin treatment and the transduction of Sirt1 in mice, whereas this phenomenon was prominently ablated by silencing of Sirt1. Notably, SIRT1 physically interacted with YY1 and attenuated YY1 occupancy on the Cyp2e1 gene promoter. Melatonin‐SIRT1 signaling ameliorates alcohol‐induced oxidative liver injury by disrupting the CRBN‐YY1‐CYP2E1 signaling pathway. The manipulation of CRBN‐YY1‐CYP2E1 signaling network by the melatonin‐SIRT1 pathway highlights a novel entry point for treating alcoholic liver disease. [ABSTRACT FROM AUTHOR]

Alcoholic liver disease is a major cause of chronic liver disease worldwide, and cannabinoid receptor type 1 ( CB1R) is involved in a diverse metabolic diseases. B-cell translocation gene 2 ( BTG2) and yin yang 1 ( YY1) are a potent regulator of biological conditions. Melatonin plays a crucial role in regulating diverse physiological functions and metabolic homeostasis. Micro RNAs are key regulators of various biological processes. Herein, we demonstrate that melatonin improves bile acid synthesis in the liver of alcohol-fed mice by controlling miR-497 expression. The level of bile acid and the expression of Cb1r, Btg2, Yy1, and bile acid synthetic enzymes were significantly elevated in the livers of Lieber-DeCarli alcohol-fed mice. The overexpression of Btg2 enhanced Yy1 gene expression and bile acid production, whereas disrupting the CB1R- BTG2- YY1 cascade protected against the bile acid synthesis caused by alcohol challenge. We identified an alcohol-mediated YY1 binding site on the cholesterol 7α-hydroxylase ( Cyp7a1) gene promoter using promoter deletion analysis and chromatin immunoprecipitation assays. Notably, melatonin attenuated the alcohol-stimulated induction of Btg2, Yy1 mRNA levels and bile acid production by promoting miR-497. Overexpression of a miR-497 mimic dramatically diminished the increase of Btg2 and Yy1 gene expression as well as bile acid production by alcohol, whereas this phenomenon was reversed by miR-497 inhibitor. These results demonstrate that the upregulation of miR-497 by melatonin represses alcohol-induced bile acid synthesis by attenuating the BTG2- YY1 signaling pathway. The melatonin-miR497 signaling network may provide novel therapeutic targets for the treatment of hepatic metabolic dysfunction caused by the alcohol-dependent pathway. [ABSTRACT FROM AUTHOR]

In response to microbial infection, expression of the defensin-like peptide hepcidin (encoded by Hamp) is induced in hepatocytes to decrease iron release from macrophages. To elucidate the mechanism by which Salmonella enterica var. Typhimurium (S. typhimurium), an intramacrophage bacterium, alters host iron metabolism for its own survival, we examined the role of nuclear receptor family members belonging to the NR3B subfamily in mouse hepatocytes. Here, we report that estrogen-related receptor γ (ERRγ, encoded by Esrrg) modulates the intramacrophage proliferation of S. typhimurium by altering host iron homeostasis, and we demonstrate an antimicrobial effect of an ERRγ inverse agonist. Hepatic ERRγ expression was induced by S. typhimurium-stimulated interleukin-6 signaling, resulting in an induction of hepcidin and eventual hypoferremia in mice. Conversely, ablation of ERRγ mRNA expression in liver attenuated the S. typhimurium-mediated induction of hepcidin and normalized the hypoferremia caused by S. typhimurium infection. An inverse agonist of ERRγ ameliorated S. typhimurium-mediated hypoferremia through reduction of ERRγ-mediated hepcidin mRNA expression and exerted a potent antimicrobial effect on the S. typhimurium infection, thereby improving host survival. Taken together, these findings suggest an alternative approach to control multidrug-resistant intracellular bacteria by modulating host iron homeostasis. [ABSTRACT FROM AUTHOR]

A nonsense mutation in cereblon (CRBN) causes a mild type of mental retardation in humans. An earlier study showed that CRBN negatively regulates the functional activity of AMP-activated protein kinase (AMPK) in vitro by binding directly to the α1-subunit of the AMPK complex. However, the in vivo role of CRBN was not studied. For elucidation of the physiological functions of Crbn, a mouse strain was generated in which the Crbn gene was deleted throughout the whole body. In Crbn-deficient mice fed a normal diet, AMPK in the liver showed hyperphosphorylation, which indicated the constitutive activation of AMPK. Since Crbn-deficient mice showed significantly less weight gain when fed a high-fat diet and their insulin sensitivity was considerably improved, the functions of Crbn in the liver were primarily investigated. These results provide the first in vivo evidence that Crbn is a negative modulator of AMPK, which suggests that Crbn may be a potential target for metabolic disorders of the liver. [ABSTRACT FROM AUTHOR]

Background and Purpose Endoplasmic reticulum ( ER) stress has been implicated in the pathogeneses of insulin resistance and type 2 diabetes, and extracellular signal-regulated kinase ( ERK) antagonist is an insulin sensitizer that can restore muscle insulin responsiveness in both tunicamycin-treated muscle cells and type 2 diabetic mice. The present study was undertaken to determine whether the chemical or genetic inhibition ER stress pathway targeting by ERK results in metabolic benefits in muscle cells. Experimental Approach ER stress was induced in L6 myotubes using tunicamycin (5 μg·mL−1) or thapsigargin (300 nM) and cells were transfected with siRNA ERK or AMPKα2. Changes in ER stress and in the ERK and AMPK signalling pathways were explored by Western blotting. The phosphorylation levels of insulin receptor substrate 1 were analysed by immunoprecipitation and using glucose uptake assay. Key Results ER stress dampened insulin-stimulated signals and glucose uptake, whereas treatment with the specific ERK inhibitor U0126 (25 μM) rescued impaired insulin signalling via AMPK activation. In db/db mice, U0126 administration decreased markers of insulin resistance and increased the phosphorylations of Akt and AMPK in muscle tissues. Conclusions and Implications Inhibition of ERK signalling pathways by a chemical inhibitor and knockdown of ERK improved AMPK and Akt signallings and reversed ER stress-induced insulin resistance in L6 myotubes. These findings suggest that ERK signalling plays an important role in the regulation of insulin signals in muscle cells under ER stress. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Metformin is an antidiabetic drug commonly used to treat type 2 diabetes. The aim of the study was to determine whether metformin regulates hepatic gluconeogenesis through the orphan nuclear receptor small heterodimer partner (SHP; NR0B2). RESEARCH DESIGN AND METHODS--We assessed the regulation of hepatic SHP gene expression by Northern blot analysis with metformin and adenovirus containing a constitutive active form of AMP-activated protein kinase (AMPK) (Ad-AMPK) and evaluated SHP, PEPCK, and G6Pase promoter activities via transient transfection assays in hepatocytes. Knockdown of SHP using siRNA SHP was conducted to characterize the metformin-induced inhibition of hepatic gluconeogenic gene expression in hepatocytes, and metformin-- and adenovirus SHP (Ad-SHP)--mediated hepatic glucose production was measured in B6-Lep[sup ob/ob] mice. RESULTS--Hepatic SHP gene expression was induced by metformin, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), and Ad-AMPK. Metformin-induced SHP gene expression was abolished by adenovirus containing the dominant negative form of AMPK (Ad-DN-AMPK), as well as by compound C. Metformin inhibited hepatocyte nuclear factor-4α- or FoxA2-mediated promoter activity of PEPCK and G6Pase, and the inhibition was blocked with siRNA SHP. Additionally, SHP knockdown by adenovirus containing siRNA SHP inhibited metformin-mediated repression of cAMP/dexamethasone-induced hepatic gluconeogenic gene expression. Furthermore, oral administration of metformin increased SHP mRNA levels in B6-Lep[sup ob/ob] mice. Overexpression of SHP by Ad-SHP decreased blood glucose levels and hepatic gluconeogenic gene expression in B6-Lep[sup ob/ob] mice. CONCLUSIONS--We have concluded that metformin inhibits hepatic gluconeogenesis through AMPK-dependent regulation of SHP. Diabetes 57:306-314, 2008 [ABSTRACT FROM AUTHOR]

Nogo-A (Rtn 4A), a member of the reticulon 4 (Rtn4) protein family, is a neurite outgrowth inhibitor protein that is primarily expressed in the central nervous system (CNS). However, previous studies revealed that Nogo-A was upregulated in skeletal muscles of Amyotrophic lateral sclerosis (ALS) patients. Additionally, experiments showed that endoplasmic reticulum (ER) stress marker, C/EBP homologous protein (CHOP), was upregulated in gastrocnemius muscle of a murine model of ALS. We therefore hypothesized that Nogo-A might relate to skeletal muscle diseases. According to our knocking down and overexpression results in muscle cell line (C2C12), we have found that upregulation of Nogo-A resulted in upregulation of CHOP, pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α, while downregulation of Nogo-A led to downregulation of CHOP, IL-6 and TNF-α. Immunofluorescence results showed that Nogo-A and CHOP were expressed by myofibers as well as tissue macrophages. Since resident macrophages share similar functions as bone marrow-derived macrophages (BMDM), we therefore, isolated macrophages from bone marrow to study the role of Nogo-A in activation of these cells. Lipopolysaccharide (LPS)-stimulated BMDM in Nogo-KO mice showed low mRNA expression of CHOP, IL-6 and TNF-α compared to BMDM in wild type (WT) mice. Interestingly, Nogo knockout (KO) BMDM exhibited lower migratory activity and phagocytic ability compared with WT BMDM after LPS treatment. In addition, mice experiments data revealed that upregulation of Nogo-A in notexin- and tunicamycin-treated muscles was associated with upregulation of CHOP, IL-6 and TNF-α in WT group, while in Nogo-KO group resulted in low expression level of CHOP, IL-6 and TNF-α. Furthermore, upregulation of Nogo-A in dystrophin-deficient (mdx) murine model, myopathy and Duchenne muscle dystrophy (DMD) clinical biopsies was associated with upregulation of CHOP, IL-6 and TNF-α. To the best of our knowledge, this is the first study to demonstrate Nogo-A as a regulator of inflammation in diseased muscle and bone marrow macrophages and that deletion of Nogo-A alleviates muscle inflammation and it can be utilized as a therapeutic target for improving muscle diseases. [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]

Piperaceae plants consist of about 3600 species, of which about 2000 are Piper plants. Their habitat is distributed across pantropical regions. The representative plant is Piper nigrum, known as black pepper. These plants have been widely used in folk medicine in Korean traditional medicine. This review collected papers identifying and separating the amides obtained from these Piper plants, with a focus on Piper amides potential to control the production and growth of fungal strains that cause plant disease and their insecticidal properties against agricultural pests. Piper amide benefits include antiaflatoxigenic activities, antiparasitic activities, anticancer properties, antiplatelet activities, and anti-inflammatory activities, among other therapeutic properties for the treatment of human diseases. In addition, this review paper provides a total synthesis study on the mass production of Piper amides and their derivatives, with a formulation study for industrial use. This review paper is designed to help inform future studies on Piper amide applications. [ABSTRACT FROM AUTHOR]

In this study, the antimelanogenic activity of piperlongumine in murine B16F10 melanoma cells and zebrafish was investigated, and its mode of antimelanogenic action was elucidated using quantitative reverse transcription-polymerase chain reaction. A melanocyte-stimulating hormone (α-MSH, 200 nM) was used to induce melanin production in B16F10 melanoma cells, and kojic acid (200 μM) was used as a positive control. Piperlongumine had no inhibitory effects on cell growth at the treated concentrations (3 and 6 μM), and it significantly reduced total melanin production. Piperlongumine decreased the expression of Mitf, Tyr, Trp-1, and Trp-2 and tyrosinase activity was also dramatically reduced by the piper amide addition under α-MSH treatment. With these findings, zebrafish embryos were used to confirm antimelanogenic activity of piperlongumine, and it showed the potent antimelanogenic activity at the concentration of 1 μM. Altogether, piperlongumine has potent antimelanogenic activity, and these results support it as a candidate for natural depigmentation agent in a cosmetic and pharmaceutical industries. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 21 (FGF21) is a hormone that is vital for the regulation of metabolic homeostasis. In the present study, we report that Kruppel-like factor 15 (KLF15) is a novel mediator of b-cell translocation gene 2 (BTG2)-induced FGF21 biosynthesis. The expression levels of hepatic Fgf21, Btg2, and Klf15, and the production of serum FGF21 increased significantly in fasted and forskolin (FSK)-treated mice. The overexpression of Btg2 using an adenoviral delivery system elevated FGF21 production by upregulating Klf15 transcription. Interaction studies indicated that BTG2 was co-immunoprecipitated with KLF15 and recruited by the Fgf21 promoter. The disruption of hepatic Btg2 and Klf15 genes markedly attenuated the induction of Fgf21 expression and FGF21 biosynthesis in fasted mice. Similarly, the FSK-mediated induction of Fgf21 promoter activity was strikingly ablated by silencing of Btg2 and Klf15. Taken together, these findings suggest that KLF15 and BTG2 are mediators of fasting-induced hepatic FGF21 expression. Therefore, targeting BTG2 and KLF15 might be a therapeutically important strategy for combat metabolic dysfunction. [ABSTRACT FROM AUTHOR]