掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s13340-022-00610-0

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DOI： 10.1101/2022.09.22.509046

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Retinitis pigmentosa (RP) is a genetically heterogeneous group of inherited retinal disorders involving the progressive dysfunction of photoreceptors and the retinal pigment epithelium, for which there is currently no treatment. The rd6 mouse is a natural model of autosomal recessive retinal degeneration. Given the known contributions of oxidative stress caused by reactive oxygen species (ROS) and selective inhibition of potent ROS peroxynitrite and OH·by H2 gas we have previously demonstrated, we hypothesized that ingestion of H2 water may delay the progression of photoreceptor death in rd6 mice. H2 mice showed significantly higher retinal thickness as compared to controls on optical coherence tomography. Histopathological and morphometric analyses revealed higher thickness of the outer nuclear layer for H2 mice than controls, as well as higher counts of opsin red/green-positive cells. RNA sequencing (RNA-seq) analysis of differentially expressed genes in the H2 group versus control group revealed 1996 genes with significantly different expressions. Gene and pathway ontology analysis showed substantial upregulation of genes responsible for phototransduction in H2 mice. Our results show that drinking water high in H2 (1.2-1.6 ppm) had neuroprotective effects and inhibited photoreceptor death in mice, and suggest the potential of H2 for the treatment of RP.

DOI： 10.1038/s41598-022-17903-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Deleterious somatic mutations in DNA methyltransferase 3 alpha (DNMT3A) and TET mehtylcytosine dioxygenase 2 (TET2) are associated with clonal expansion of hematopoietic cells and higher risk of cardiovascular disease (CVD). Here, we investigated roles of DNMT3A and TET2 in normal human monocyte-derived macrophages (MDM), in MDM isolated from individuals with DNMT3A or TET2 mutations, and in macrophages isolated from human atherosclerotic plaques. We found that loss of function of DNMT3A or TET2 resulted in a type I interferon response due to impaired mitochondrial DNA integrity and activation of cGAS signaling. DNMT3A and TET2 normally maintained mitochondrial DNA integrity by regulating the expression of transcription factor A mitochondria (TFAM) dependent on their interactions with RBPJ and ZNF143 at regulatory regions of the TFAM gene. These findings suggest that targeting the cGAS-type I IFN pathway may have therapeutic value in reducing risk of CVD in patients with DNMT3A or TET2 mutations.

DOI： 10.1016/j.immuni.2022.06.022

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Immaturity of alveolar macrophages (AMs) around birth contributes to the susceptibility of newborns to lung disease. However, the molecular features differentiating neonatal and mature, adult AMs are poorly understood. In this study, we identify the unique transcriptomes and enhancer landscapes of neonatal and adult AMs in mice. Although the core AM signature was similar, murine adult AMs expressed higher levels of genes involved in lipid metabolism, whereas neonatal AMs expressed a largely proinflammatory gene profile. Open enhancer regions identified by an assay for transposase-accessible chromatin followed by high-throughput sequencing (ATAC-seq) contained motifs for nuclear receptors, MITF, and STAT in adult AMs and AP-1 and NF-κB in neonatal AMs. Intranasal LPS activated a similar innate immune response in both neonatal and adult mice, with higher basal expression of inflammatory genes in neonates. The lung microenvironment drove many of the distinguishing gene expression and open chromatin characteristics of neonatal and adult AMs. Neonatal mouse AMs retained high expression of some proinflammatory genes, suggesting that the differences in neonatal AMs result from both inherent cell properties and environmental influences.

DOI： 10.4049/jimmunol.2101192

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Regulation of gene expression requires the combinatorial binding of sequence-specific transcription factors (TFs) at promoters and enhancers. Prior studies showed that alterations in the spacing between TF binding sites can influence promoter and enhancer activity. However, the relative importance of TF spacing alterations resulting from naturally occurring insertions and deletions (InDels) has not been systematically analyzed. To address this question, we first characterized the genome-wide spacing relationships of 73 TFs in human K562 cells as determined by ChIP-seq. We found a dominant pattern of a relaxed range of spacing between collaborative factors, including 45 TFs exclusively exhibiting relaxed spacing with their binding partners. Next, we exploited millions of InDels provided by genetically diverse mouse strains and human individuals to investigate the effects of altered spacing on TF binding and local histone acetylation. These analyses suggested that spacing alterations resulting from naturally occurring InDels are generally tolerated in comparison to genetic variants directly affecting TF binding sites. To experimentally validate this prediction, we introduced synthetic spacing alterations between PU.1 and C/EBPβ binding sites at six endogenous genomic loci in a macrophage cell line. Remarkably, collaborative binding of PU.1 and C/EBPβ at these locations tolerated changes in spacing ranging from 5-bp increase to >30-bp decrease. Collectively, these findings have implications for understanding mechanisms underlying enhancer selection and for the interpretation of non-coding genetic variation.

DOI： 10.7554/eLife.70878

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Integrative analysis of next-generation sequencing data can help understand disease mechanisms. Specifically, ChIP-seq can illuminate where transcription regulators bind to regulate transcription. A major obstacle to performing this assay on primary cells is the low numbers obtained from tissues. The extensively validated ChIP-seq protocol presented here uses small volumes and single-pot on-bead library preparation to generate diverse high-quality ChIP-seq data. This protocol allows for medium-to-high-throughput ChIP-seq of low-abundance cells and can also be applied to other mammalian cells. For complete details on the use and execution of this protocol, please refer to Brigidi et al. (2019), Carlin et al. (2018), Heinz et al. (2018), Nott et al. (2019), Sakai et al. (2019), and Seidman et al. (2020).

DOI： 10.1016/j.xpro.2021.100358

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Significant advancements in understanding disease mechanisms can occur through combined analysis of next-generation sequencing datasets generated using purified cell populations. Here, we detail our optimized protocol for purification of mouse hepatic macrophages (or other liver non-parenchymal populations) suitable for use in various next-generation sequencing protocols. An alternative framework is described for sorting pre-fixed hepatic nuclei populations. This strategy has the advantage of rapidly preserving the nuclei and can facilitate success with ChIP-seq for more challenging molecules. For complete details on the use and execution of these protocols, please refer to Muse et al. (2018), Sakai et al. (2019), and Seidman et al. (2020).

DOI： 10.1016/j.xpro.2021.100363

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Kupffer cells, the resident macrophages of the liver, comprise the largest pool of tissue macrophages in the body. Within the liver sinusoids Kupffer cells perform functions common across many tissue macrophages including response to tissue damage and antigen presentation. They also engage in specialized activities including iron scavenging and the uptake of opsonized particles from the portal blood. Here, we review recent studies of the epigenetic pathways that establish Kupffer cell identity and function. We describe a model by which liver-environment specific signals induce lineage determining transcription factors necessary for differentiation of Kupffer cells from bone-marrow derived monocytes. We conclude by discussing how these lineage determining transcription factors (LDTFs) drive Kupffer cell behavior during both homeostasis and disease, with particular focus on the relevance of Kupffer cell LDTF pathways in the setting of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis.

DOI： 10.3389/fimmu.2020.609618

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記述言語：英語  

Osteoclasts are the exclusive bone-resorbing cells, playing a central role in bone metabolism, as well as the bone damage that occurs under pathological conditions1,2. In postnatal life, haematopoietic stem-cell-derived precursors give rise to osteoclasts in response to stimulation with macrophage colony-stimulating factor and receptor activator of nuclear factor-κB ligand, both of which are produced by osteoclastogenesis-supporting cells such as osteoblasts and osteocytes1-3. However, the precise mechanisms underlying cell fate specification during osteoclast differentiation remain unclear. Here, we report the transcriptional profiling of 7,228 murine cells undergoing in vitro osteoclastogenesis, describing the stepwise events that take place during the osteoclast fate decision process. Based on our single-cell transcriptomic dataset, we find that osteoclast precursor cells transiently express CD11c, and deletion of receptor activator of nuclear factor-κB specifically in CD11c-expressing cells inhibited osteoclast formation in vivo and in vitro. Furthermore, we identify Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (Cited2) as the molecular switch triggering terminal differentiation of osteoclasts, and deletion of Cited2 in osteoclast precursors in vivo resulted in a failure to commit to osteoclast fate. Together, the results of this study provide a detailed molecular road map of the osteoclast differentiation process, refining and expanding our understanding of the molecular mechanisms underlying osteoclastogenesis.

DOI： 10.1038/s42255-020-00318-y

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Society for Biochemistry & Molecular Biology (ASBMB)  

General control nonderepressible 5 (GCN5, also known as Kat2a) and p300/CBP-associated factor (PCAF, also known as Kat2b) are two homologous acetyltransferases. Both proteins share similar domain architecture consisting of a PCAF N-terminal (PCAF_N) domain, acetyltransferase domain, and a bromodomain. PCAF also acts as a ubiquitin E3 ligase whose activity is attributable to the PCAF_N domain, but its structural aspects are largely unknown. Here, we demonstrated that GCN5 exhibited ubiquitination activity in a similar manner to PCAF and its activity was supported by the ubiquitin-conjugating enzyme UbcH5. Moreover, we determined the crystal structure of the PCAF_N domain at 1.8 Å resolution and found that PCAF_N domain folds into a helical structure with a characteristic binuclear zinc region, which was not predicted from sequence analyses. The zinc region is distinct from known E3 ligase structures, suggesting this region may form a new class of E3 ligase. Our biochemical and structural study provides new insight into not only the functional significance of GCN5 but also into ubiquitin biology.

DOI： 10.1074/jbc.ra120.013431

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tissue-resident and recruited macrophages contribute to both host defense and pathology. Multiple macrophage phenotypes are represented in diseased tissues, but we lack deep understanding of mechanisms controlling diversification. Here, we investigate origins and epigenetic trajectories of hepatic macrophages during diet-induced non-alcoholic steatohepatitis (NASH). The NASH diet induced significant changes in Kupffer cell enhancers and gene expression, resulting in partial loss of Kupffer cell identity, induction of Trem2 and Cd9 expression, and cell death. Kupffer cell loss was compensated by gain of adjacent monocyte-derived macrophages that exhibited convergent epigenomes, transcriptomes, and functions. NASH-induced changes in Kupffer cell enhancers were driven by AP-1 and EGR that reprogrammed LXR functions required for Kupffer cell identity and survival to instead drive a scar-associated macrophage phenotype. These findings reveal mechanisms by which disease-associated environmental signals instruct resident and recruited macrophages to acquire distinct gene expression programs and corresponding functions.

DOI： 10.1016/j.immuni.2020.04.001

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tissue environment plays a powerful role in establishing and maintaining the distinct phenotypes of resident macrophages, but the underlying molecular mechanisms remain poorly understood. Here, we characterized transcriptomic and epigenetic changes in repopulating liver macrophages following acute Kupffer cell depletion as a means to infer signaling pathways and transcription factors that promote Kupffer cell differentiation. We obtained evidence that combinatorial interactions of the Notch ligand DLL4 and transforming growth factor-b (TGF-β) family ligands produced by sinusoidal endothelial cells and endogenous LXR ligands were required for the induction and maintenance of Kupffer cell identity. DLL4 regulation of the Notch transcriptional effector RBPJ activated poised enhancers to rapidly induce LXRα and other Kupffer cell lineage-determining factors. These factors in turn reprogrammed the repopulating liver macrophage enhancer landscape to converge on that of the original resident Kupffer cells. Collectively, these findings provide a framework for understanding how macrophage progenitor cells acquire tissue-specific phenotypes.

DOI： 10.1016/j.immuni.2019.09.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Nature  

Mechanisms by which members of the AP-1 family of transcription factors play non-redundant biological roles despite recognizing the same DNA sequence remain poorly understood. To address this question, here we investigate the molecular functions and genome-wide DNA binding patterns of AP-1 family members in primary and immortalized mouse macrophages. ChIP-sequencing shows overlapping and distinct binding profiles for each factor that were remodeled following TLR4 ligation. Development of a machine learning approach that jointly weighs hundreds of DNA recognition elements yields dozens of motifs predicted to drive factor-specific binding profiles. Machine learning-based predictions are confirmed by analysis of the effects of mutations in genetically diverse mice and by loss of function experiments. These findings provide evidence that non-redundant genomic locations of different AP-1 family members in macrophages largely result from collaborative interactions with diverse, locus-specific ensembles of transcription factors and suggest a general mechanism for encoding functional specificities of their common recognition motif.

DOI： 10.1038/s41467-018-08236-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Nature America, Inc  

Glucagon-mediated gene transcription in the liver is critical for maintaining glucose homeostasis. Promoting the induction of gluconeogenic genes and blocking that of insulin receptor substrate (Irs)2 in hepatocytes contributes to the pathogenesis of type 2 diabetes. However, the molecular mechanism by which glucagon signalling regulates hepatocyte metabolism is not fully understood. We previously showed that a fasting-inducible signalling module consisting of general control non-repressed protein 5, co-regulator cAMP response element-binding protein binding protein/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2, and protein kinase A is required for glucagon-induced transcription of gluconeogenic genes. The present study aimed to identify the downstream effectors of this module in hepatocytes by examining glucagon-induced potential target genes. One of these genes was prolyl hydroxylase domain (PHD)3, which suppressed stress signalling through inhibition of the IκB kinase-nuclear factor-κB pathway in a proline hydroxylase-independent manner to maintain insulin signalling. PHD3 was also required for peroxisome proliferator-activated receptor γ coactivator 1α-induced gluconeogenesis, which was dependent on proline hydroxylase activity, suggesting that PHD3 regulates metabolism in response to glucagon as well as insulin. These findings demonstrate that glucagon-inducible PHD3 regulates glucose metabolism by suppressing stress signalling and optimising gluconeogenesis and insulin signalling in hepatocytes.

DOI： 10.1038/s41598-018-32575-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier {BV}  

Non-coding genetic variation is a major driver of phenotypic diversity and allows the investigation of mechanisms that control gene expression. Here, we systematically investigated the effects of >50 million variations from five strains of mice on mRNA, nascent transcription, transcription start sites, and transcription factor binding in resting and activated macrophages. We observed substantial differences associated with distinct molecular pathways. Evaluating genetic variation provided evidence for roles of ∼100 TFs in shaping lineage-determining factor binding. Unexpectedly, a substantial fraction of strain-specific factor binding could not be explained by local mutations. Integration of genomic features with chromatin interaction data provided evidence for hundreds of connected cis-regulatory domains associated with differences in transcription factor binding and gene expression. This system and the >250 datasets establish a substantial new resource for investigation of how genetic variation affects cellular phenotypes.

DOI： 10.1016/j.cell.2018.04.018

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Nature  

Liver metabolism undergoes robust circadian oscillations in gene expression and enzymatic activity essential for liver homeostasis, but whether the circadian clock controls homeostatic self-renewal of hepatocytes is unknown. Here we show that hepatocyte polyploidization is markedly accelerated around the central vein, the site of permanent cell self-renewal, in mice deficient in circadian Period genes. In these mice, a massive accumulation of hyperpolyploid mononuclear and binuclear hepatocytes occurs due to impaired mitogen-activated protein kinase phosphatase 1 (Mkp1)-mediated circadian modulation of the extracellular signal-regulated kinase (Erk1/2) activity. Time-lapse imaging of hepatocytes suggests that the reduced activity of Erk1/2 in the midbody during cytokinesis results in abscission failure, leading to polyploidization. Manipulation of Mkp1 phosphatase activity is sufficient to change the ploidy level of hepatocytes. These data provide clear evidence that the Period genes not only orchestrate dynamic changes in metabolic activity, but also regulate homeostatic self-renewal of hepatocytes through Mkp1-Erk1/2 signaling pathway.

DOI： 10.1038/s41467-017-02207-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Nature  

Hepatic gluconeogenesis during fasting results from gluconeogenic gene activation via the glucagon-cAMP-protein kinase A (PKA) pathway, a process whose dysregulation underlies fasting hyperglycemia in diabetes. Such transcriptional activation requires epigenetic changes at promoters by mechanisms that have remained unclear. Here we show that GCN5 functions both as a histone acetyltransferase (HAT) to activate fasting gluconeogenesis and as an acetyltransferase for the transcriptional co-activator PGC-1α to inhibit gluconeogenesis in the fed state. During fasting, PKA phosphorylates GCN5 in a manner dependent on the transcriptional coregulator CITED2, thereby increasing its acetyltransferase activity for histone and attenuating that for PGC-1α. This substrate switch concomitantly promotes both epigenetic changes associated with transcriptional activation and PGC-1α-mediated coactivation, thereby triggering gluconeogenesis. The GCN5-CITED2-PKA signalling module and associated GCN5 substrate switch thus serve as a key driver of gluconeogenesis. Disruption of this module ameliorates hyperglycemia in obese diabetic animals, offering a potential therapeutic strategy for such conditions.

DOI： 10.1038/ncomms13147

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier {BV}  

Hematopoietic stem cells (HSCs) maintain quiescence by activating specific metabolic pathways, including glycolysis. We do not yet have a clear understanding of how this metabolic activity changes during stress hematopoiesis, such as bone marrow transplantation. Here, we report a critical role for the p38MAPK family isoform p38α in initiating hematopoietic stem and progenitor cell (HSPC) proliferation during stress hematopoiesis in mice. We found that p38MAPK is immediately phosphorylated in HSPCs after a hematological stress, preceding increased HSPC cycling. Conditional deletion of p38α led to defective recovery from hematological stress and a delay in initiation of HSPC proliferation. Mechanistically, p38α signaling increases expression of inosine-5'-monophosphate dehydrogenase 2 in HSPCs, leading to altered levels of amino acids and purine-related metabolites and changes in cell-cycle progression in vitro and in vivo. Our studies have therefore uncovered a p38α-mediated pathway that alters HSPC metabolism to respond to stress and promote recovery.

DOI： 10.1016/j.stem.2016.05.013

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Publishing Group  

During fasting, induction of hepatic gluconeogenesis is crucial to ensure proper energy homeostasis. Such induction is dysregulated in type 2 diabetes, resulting in the development of fasting hyperglycemia. Hormonal and nutrient regulation of metabolic adaptation during fasting is mediated predominantly by the transcriptional coactivator peroxisome proliferative activated receptor γ coactivator 1α (PGC-1α) in concert with various other transcriptional regulators. Although CITED2 (CBP- and p300-interacting transactivator with glutamic acid- and aspartic acid-rich COOH-terminal domain 2) interacts with many of these molecules, the role of this protein in the regulation of hepatic gluconeogenesis was previously unknown. Here we show that CITED2 is required for the regulation of hepatic gluconeogenesis through PGC-1α. The abundance of CITED2 was increased in the livers of mice by fasting and in cultured hepatocytes by glucagon-cAMP-protein kinase A (PKA) signaling, and the amount of CITED2 in liver was higher in mice with type 2 diabetes than in non-diabetic mice. CITED2 inhibited the acetylation of PGC-1α by blocking its interaction with the acetyltransferase general control of amino acid synthesis 5-like 2 (GCN5). The consequent downregulation of PGC-1α acetylation resulted in an increase in its transcriptional coactivation activity and an increased expression of gluconeogenic genes. The interaction of CITED2 with GCN5 was disrupted by insulin in a manner that was dependent on phosphoinositide 3-kinase (PI3K)-thymoma viral proto-oncogene (Akt) signaling. Our results show that CITED2 functions as a transducer of glucagon and insulin signaling in the regulation of PGC-1α activity that is associated with the transcriptional control of gluconeogenesis and that this function is mediated through the modulation of GCN5-dependent PGC-1α acetylation. We also found that loss of hepatic CITED2 function suppresses gluconeogenesis in diabetic mice, suggesting it as a therapeutic target for hyperglycemia.

DOI： 10.1038/nm.2691

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Bio-Protocol, {LLC}  

DOI： 10.21769/bioprotoc.284

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Society for Biochemistry {\&} Molecular Biology ({ASBMB})  

Krüppel-like factor 15 (KLF15), a member of the Krüppel-like factor family of transcription factors, has been found to play diverse roles in adipocytes in vitro. However, little is known of the function of KLF15 in adipocytes in vivo. We have now found that the expression of KLF15 in adipose tissue is down-regulated in obese mice, and we therefore generated adipose tissue-specific KLF15 transgenic (aP2-KLF15 Tg) mice to investigate the possible contribution of KLF15 to various pathological conditions associated with obesity in vivo. The aP2-KLF15 Tg mice manifest insulin resistance and are resistant to the development of obesity induced by maintenance on a high fat diet. However, they also exhibit improved glucose tolerance as a result of enhanced insulin secretion. Furthermore, this enhancement of insulin secretion was shown to result from down-regulation of the expression of stearoyl-CoA desaturase 1 (SCD1) in white adipose tissue and a consequent reduced level of oxidative stress. This is supported by the findings that restoration of SCD1 expression in white adipose tissue of aP2-KLF15 Tg mice exhibited increased oxidative stress in white adipose tissue and reduced insulin secretion with hyperglycemia. Our data thus provide an example of cross-talk between white adipose tissue and pancreatic β cells mediated through modulation of oxidative stress.

DOI： 10.1074/jbc.M111.242651

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：The Endocrine Society  

Physical exercise ameliorates metabolic disorders such as type 2 diabetes mellitus and obesity, but the molecular basis of these effects remains elusive. In the present study, we found that exercise up-regulates heparin-binding epidermal growth factor-like growth factor (HB-EGF) in skeletal muscle. To address the metabolic consequences of such gain of HB-EGF function, we generated mice that overexpress this protein specifically in muscle. The transgenic animals exhibited a higher respiratory quotient than did wild-type mice during indirect calorimetry, indicative of their selective use of carbohydrate rather than fat as an energy substrate. They also showed substantial increases in glucose tolerance, insulin sensitivity, and glucose uptake by skeletal muscle. These changes were accompanied by increased kinase activity of Akt in skeletal muscle and consequent inhibition of Forkhead box O1-dependent expression of the pyruvate dehydrogenase kinase 4 gene. Furthermore, mice with a high level of transgene expression were largely protected from obesity, hepatic steatosis, and insulin resistance, even when maintained on a high-fat diet. Our results suggest that HB-EGF produced by contracting muscle acts as an insulin sensitizer that facilitates peripheral glucose disposal.

DOI： 10.1210/en.2008-1647

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier {BV}  

The transcriptional regulator peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) controls mitochondrial biogenesis and energy homeostasis. Although physical exercise induces PGC-1alpha expression in muscle, the underlying mechanism of this effect has remained incompletely understood. We recently identified a novel muscle-enriched isoform of PGC-1alpha transcript (designated PGC-1alpha-b) that is derived from a previously unidentified first exon. We have now cloned and characterized the human PGC-1alpha-b promoter. The muscle-specific transcription factors MyoD and MRF4 transactivated this promoter through interaction with a proximal E-box motif. Furthermore, either forced expression of Ca(2+)- and calmodulin-dependent protein kinase IV (CaMKIV), calcineurin A, or the p38 mitogen-activated protein kinase (p38 MAPK) kinase MKK6 or the intracellular accumulation of cAMP activated the PGC-1alpha-b promoter in cultured myoblasts through recruitment of cAMP response element (CRE)-binding protein (CREB) to a putative CRE located downstream of the E-box. Our results thus reveal a potential molecular basis for isoform-specific regulation of PGC-1alpha expression in contracting muscle.

DOI： 10.1016/j.bbrc.2009.02.077

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier {BV}  

In patients with various catabolic conditions, glucocorticoid excess induces skeletal muscle wasting by accelerating protein degradation via the ubiquitin-proteasome pathway. Although the transcriptional coactivator p300 has been implicated in this pathological process, regulatory mechanisms and molecular targets of its action remain unclear. Here we show that CREB-binding protein (CBP)/p300-interacting transactivator with ED-rich tail 2 (Cited2), which binds to the cysteine-histidine-rich region 1 of p300 and CBP, regulates muscle mass in vitro. Adenovirus-mediated overexpression of wild-type Cited2 significantly blocked morphological alterations of C2C12 myotubes with a concomitant decrease in myosin heavy chain protein in response to synthetic glucocorticoid dexamethasone, which were attributable to the reduced induction of atrophy-related ubiquitin ligases MuRF1 and MAFbx. These myotube-sparing effects were less pronounced, however, with a carboxyl-terminally truncated mutant of Cited2 that lacked the ability to bind p300. These results suggest that the gain of Cited2 function counteracts glucocorticoid-induced muscle atrophy through inhibition of proteolysis mediated by p300-dependent gene transcription.

DOI： 10.1016/j.bbrc.2008.11.062

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Publishing Group  

Insulin receptor substrate (IRS)-1 and IRS-2 have dominant roles in the action of insulin, but other substrates of the insulin receptor kinase, such as Gab1, c-Cbl, SH2-B and APS, are also of physiological relevance. Although the protein downstream of tyrosine kinases-1 (Dok1) is known to function as a multisite adapter molecule in insulin signaling, its role in energy homeostasis has remained unclear. Here we show that Dok1 regulates adiposity. Expression of Dok1 in white adipose tissue was markedly increased in mice fed a high-fat diet, whereas adipocytes lacking this adapter were smaller and showed a reduced hypertrophic response to this dietary manipulation. Dok1-deficient mice were leaner and showed improved glucose tolerance and insulin sensitivity compared with wild-type mice. Embryonic fibroblasts from Dok1-deficient mice were impaired in adipogenic differentiation, and this defect was accompanied by an increased activity of the protein kinase ERK and a consequent increase in the phosphorylation of peroxisome proliferator-activated receptor (PPAR)-gamma on Ser112. Mutation of this negative regulatory site for the transactivation activity of PPAR-gamma blocked development of the lean phenotype caused by Dok1 ablation. These results indicate that Dok1 promotes adipocyte hypertrophy by counteracting the inhibitory effect of ERK on PPAR-gamma and may thus confer predisposition to diet-induced obesity.

DOI： 10.1038/nm1706

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記述言語：日本語   出版者・発行元：(一社)日本脳循環代謝学会  

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記述言語：日本語   出版者・発行元：(一社)日本脳循環代謝学会  

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記述言語：日本語   出版者・発行元：(一社)日本脳循環代謝学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本抗加齢医学会  

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記述言語：日本語   出版者・発行元：(一社)日本抗加齢医学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

NASHでは、循環中の単球が肝臓に遊走して複数のマクロファージ集団を形成し、炎症・線維化の進展に関与する。そこで、筆者らは、肝臓由来シグナルによる単球のリプログラミング機構の解明を試みた。肝類洞における肝臓マクロファージの分化には、Notch-RBPJシグナルおよびTGF-β/BMP-SMADシグナルの活性化と、肝細胞由来の内因性LXRアゴニストが必要と考えられた。また、NASHにおいては、クッパー細胞のエンハンサー活性の変化と、新規に肝臓に誘導された単球の肝臓の微小環境依存的なクロマチンリモデリングにより、異なる遺伝子発現を示す4つのマクロファージ集団が形成されることが明らかとなった。つまり、NASHにおける疾患特異的なマクロファージは、単球・マクロファージがニッシェ特異的にリプログラミングされることで出現すると考えられた。(著者抄録)

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記述言語：日本語   出版者・発行元：(株)羊土社  

NASHでは、肝臓へ単球が遊走して多様なマクロファージ集団を形成する。NASHモデルにおける肝臓マクロファージのゲノミクス解析から、NASHの肝臓では、クッパー細胞のエンハンサー活性の変化と、新たに肝臓に誘導された単球の肝臓の微小環境依存的なクロマチンリモデリングにより、異なる遺伝子発現を示す4つのマクロファージ集団が形成されること、クッパー細胞が細胞死を起こして減少し、単球由来マクロファージで置換されることが明らかとなってきた。今後、NASHの病態進展における、各マクロファージ集団の役割の解明が期待される。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

NASHでは、循環中の単球が肝臓に遊走して複数のマクロファージ集団を形成し、炎症・線維化の進展に関与する。そこで、筆者らは、肝臓由来シグナルによる単球のリプログラミング機構の解明を試みた。肝類洞における肝臓マクロファージの分化には、Notch-RBPJシグナルおよびTGF-β/BMP-SMADシグナルの活性化と、肝細胞由来の内因性LXRアゴニストが必要と考えられた。また、NASHにおいては、クッパー細胞のエンハンサー活性の変化と、新規に肝臓に誘導された単球の肝臓の微小環境依存的なクロマチンリモデリングにより、異なる遺伝子発現を示す4つのマクロファージ集団が形成されることが明らかとなった。つまり、NASHにおける疾患特異的なマクロファージは、単球・マクロファージがニッシェ特異的にリプログラミングされることで出現すると考えられた。(著者抄録)

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記述言語：日本語   出版者・発行元：(株)羊土社  

NASHでは、肝臓へ単球が遊走して多様なマクロファージ集団を形成する。NASHモデルにおける肝臓マクロファージのゲノミクス解析から、NASHの肝臓では、クッパー細胞のエンハンサー活性の変化と、新たに肝臓に誘導された単球の肝臓の微小環境依存的なクロマチンリモデリングにより、異なる遺伝子発現を示す4つのマクロファージ集団が形成されること、クッパー細胞が細胞死を起こして減少し、単球由来マクロファージで置換されることが明らかとなってきた。今後、NASHの病態進展における、各マクロファージ集団の役割の解明が期待される。(著者抄録)

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記述言語：日本語   出版者・発行元：上原記念生命科学財団  

CiNii Research

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記述言語：英語   出版者・発行元：(公社)日本生化学会  

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記述言語：英語   出版者・発行元：(公社)日本生化学会  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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記述言語：日本語   出版者・発行元：(一社)日本門脈圧亢進症学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(公財)日本応用酵素協会  

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

DOI： 10.1272/manms.16.213

CiNii Research

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記述言語：日本語   出版者・発行元：日本医科大学医学会  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J04260&link_issn=&doc_id=20201204310007&doc_link_id=10.1272%2Fmanms.16.213&url=https%3A%2F%2Fdoi.org%2F10.1272%2Fmanms.16.213&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：日本語   出版者・発行元：(公社)日本生化学会  

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記述言語：日本語   出版者・発行元：(公社)日本生化学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬学会  

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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J-GLOBAL

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J-GLOBAL

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記述言語：日本語   出版者・発行元：生命科学系学会合同年次大会運営事務局  

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記述言語：日本語   出版者・発行元：生命科学系学会合同年次大会運営事務局  

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(株)アークメディア  

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

ヒストンアセチル化酵素によるヒストンアセチル化は、転写活性化に重要である。筆者らはGCN5が肝糖新生系酵素の発現誘導に必須のヒストンアセチル化酵素であることを見出した。また、絶食時の肝臓でGCN5はGCN5-CITED2-PKAモジュールを形成し、同モジュールで起こるPKA依存的なGCN5 Ser275リン酸化がGCN5の基質をPGC-1αからヒストンH3へとスイッチさせ、糖新生系酵素発現を誘導することを明らかにした。肥満・糖尿病モデルマウスの肝臓におけるGCN5 Ser275リン酸化の抑制により、高血糖が改善したことから、GCN5-CITED2-PKAモジュールは、糖尿病における肝糖新生の亢進の治療ターゲットとなりうることが示された。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：(公財)日本応用酵素協会  

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J-GLOBAL

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記述言語：日本語   出版者・発行元：(株)羊土社  

ヒトは絶食状態にあっても、体内からATP合成の原料となる栄養素を調達し、各組織の需要に合わせてこれを分配してエネルギー需要を満たすことができる。長期間の生存を可能にする本プロセスが「絶食応答」であり、肝臓における糖新生やケトン体全成、多くの臓器における脂肪酸酸化の活性化が中心的な役割を果たしている。多くの酵素の遺伝子転写がホルモンによって誘導され、これらの代謝経路が活性化される。近年、本転写誘導を担う転写複合体やアセチル化をはじめとするヒストン修飾制御に関する知見の集積とともに、両者を統合する精緻な分子機構も解明されようとしている。(著者抄録)

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記述言語：日本語   出版者・発行元：(公社)日本生化学会  

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(公社)日本生化学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：英語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：(公財)日本応用酵素協会  

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記述言語：日本語   出版者・発行元：(株)中外医学社  

肝臓での糖新生は,一連の糖新生系酵素によって非糖質からグルコースを新規合成する,絶食時の低血糖の防止に不可欠な反応である.一方,糖尿病において肝糖新生は病的に亢進し,空腹時ならびに食後の高血糖を惹起している.肝糖新生の抑制は病態に即した糖尿病治療戦略であり,メトホルミンに次ぐ,これを標的とする糖尿病治療薬の開発にあたり分子機構の解明が重要な課題となっている.肝糖新生量は,グリセロール・乳酸などの基質の供給,細胞内ATPレベル,糖新生系酵素活性により規定される.近年これらの因子を,ホルモン・栄養素・代謝産物が,遺伝子転写やアロステリックな調節を介して精緻に制御していることが明らかとなっている.本稿では,ホルモンや代謝環境の変化による肝糖新生制御の分子機構について,糖新生系酵素の遺伝子発現調節を中心に最近の知見を概説する.また薬物治療標的として期待される分子や調節経路についても紹介する.(著者抄録)

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J-GLOBAL

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記述言語：日本語   出版者・発行元：(公社)日本生化学会  

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記述言語：日本語   出版者・発行元：(一社)日本病態栄養学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(公財)日本応用酵素協会  

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記述言語：日本語   出版者・発行元：(株)メディカルレビュー社  

ヒトは食事からのエネルギー源の供給が絶たれても、"飢餓応答"のシステムを起動させることにより生命活動の維持に必要なエネルギーを長期間得ることができる。本システムでは、脳などのグルコース要求性の高い臓器にこれを優先的に供給するために、他臓器におけるエネルギー源をグルコースから遊離脂肪酸(FFA)、ケトン体へシフトさせる。同時に肝臓・脂肪組織から、グルコース、ケトン体、FFAを動員し、臓器ごとの要求に応じてエネルギー源として供給する。グルカゴンやカテコラミンなどのインスリン拮抗ホルモンが、これらの応答を担っている。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本病態栄養学会  

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病合併症学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(公財)日本応用酵素協会  

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(株)協和企画  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：医歯薬出版(株)  

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2013&ichushi_jid=J00060&link_issn=&doc_id=20130423020010&doc_link_id=issn%3D0039-2359%26volume%3D245%26issue%3D3%26spage%3D260&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0039-2359%26volume%3D245%26issue%3D3%26spage%3D260&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：(公財)日本応用酵素協会  

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記述言語：日本語   出版者・発行元：メディカルレビュー社  

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(公財)日本応用酵素協会  

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(一社)日本肥満学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

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記述言語：英語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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記述言語：日本語   出版者・発行元：日本臨床分子医学会  

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記述言語：日本語   出版者・発行元：(一社)日本糖尿病学会  

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開催年月日： 2019年12月

会議種別：シンポジウム・ワークショップ パネル（指名）  

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開催年月日： 2019年7月

記述言語：英語  

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開催年月日： 2019年7月

記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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開催年月日： 2019年7月

記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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開催年月日： 2019年5月

会議種別：口頭発表（一般）  

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開催年月日： 2019年2月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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開催年月日： 2018年10月

会議種別：ポスター発表  

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開催年月日： 2016年1月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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開催年月日： 2015年10月

記述言語：英語   会議種別：口頭発表（一般）  

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開催年月日： 2015年7月

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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開催年月日： 2015年2月

会議種別：シンポジウム・ワークショップ パネル（公募）  

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開催年月日： 2014年12月

会議種別：シンポジウム・ワークショップ パネル（公募）  

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開催年月日： 2014年9月

記述言語：英語  

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開催年月日： 2014年4月

会議種別：シンポジウム・ワークショップ パネル（指名）  

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開催年月日： 2013年9月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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開催年月日： 2011年12月

会議種別：シンポジウム・ワークショップ パネル（公募）  

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開催年月日： 2011年9月

会議種別：口頭発表（一般）  

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開催年月日： 2010年12月

会議種別：シンポジウム・ワークショップ パネル（公募）  

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開催年月日： 2010年11月

記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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会議種別：シンポジウム・ワークショップ パネル（指名）  

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会議種別：シンポジウム・ワークショップ パネル（指名）  

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会議種別：シンポジウム・ワークショップ パネル（指名）  

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会議種別：シンポジウム・ワークショップ パネル（指名）  

researchmap

会議種別：シンポジウム・ワークショップ パネル（指名）  

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会議種別：シンポジウム・ワークショップ パネル（指名）  

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