Publications by authors named "Juro Sakai"

Article Synopsis
  • β-adrenergic (β-AR) signaling triggers fight-or-flight responses, enhancing functions like heart and lung performance, metabolism, and muscle contraction.
  • Recent studies challenge the traditional view of β-AR signaling as short-lived, revealing its role in long-term effects like cell differentiation and epigenomic changes.
  • The chapter examines how cold stress influences adipose tissues through β-AR signaling, emphasizing the dual role of the histone demethylase JMJD1A in managing both immediate and prolonged thermogenic responses.
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  • - Acetate, a short-chain fatty acid produced by gut microbiota, is vital for intestinal health and may influence muscle performance, yet its specific effects during resistance exercise are not fully understood.
  • - A study on mice revealed that antibiotic treatment lowered grip strength and muscle fiber size, while acetate supplementation helped counteract these negative effects, suggesting a protective role for acetate in muscle preservation.
  • - Low-fiber diets and the absence of acetyl-CoA synthase 2 in mice also led to reduced muscle size and lifespan, reinforcing the idea that acetate from gut bacteria is essential for maintaining skeletal muscle health.
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  • Mitochondria are crucial for non-shivering thermogenesis in brown and subcutaneous white adipose tissues (BAT and scWAT), but the specific mechanisms regulating mitochondrial function in these areas are still not fully understood.
  • The study shows that prolonged β-adrenergic signaling leads to epigenetic changes in scWAT that enhance mitochondrial function through the action of a histone demethylase called JMJD1A.
  • Disrupting JMJD1A in mice hampers mitochondrial biogenesis in scWAT, resulting in decreased energy expenditure and increased risks for obesity and metabolic disorders, while its role is less critical in BAT during cold stress.
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The nuclear receptor corepressor (NCoR) forms a complex with histone deacetylase 3 (HDAC3) that mediates repressive functions of unliganded nuclear receptors and other transcriptional repressors by deacetylation of histone substrates. Recent studies provide evidence that NCoR/HDAC3 complexes can also exert coactivator functions in brown adipocytes by deacetylating and activating PPARγ coactivator 1α (PGC1α) and that signaling via receptor activator of nuclear factor kappa-B (RANK) promotes the formation of a stable NCoR/HDAC3/PGC1β complex that coactivates nuclear factor kappa-B (NFκB)- and activator protein 1 (AP-1)-dependent genes required for osteoclast differentiation. Here, we demonstrate that activation of Toll-like receptor (TLR) 4, but not TLR3, the interleukin 4 (IL4) receptor nor the Type I interferon receptor, also promotes assembly of an NCoR/HDAC3/PGC1β coactivator complex.

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Organisms must adapt to environmental stresses to ensure their survival and prosperity. Different types of stresses, including thermal, mechanical, and hypoxic stresses, can alter the cellular state that accompanies changes in gene expression but not the cellular identity determined by a chromatin state that remains stable throughout life. Some tissues, such as adipose tissue, demonstrate remarkable plasticity and adaptability in response to environmental cues, enabling reversible cellular identity changes; however, the mechanisms underlying these changes are not well understood.

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Bone marrow-derived cells (BMDCs) infiltrate hypoxic tumors at a pre-angiogenic state and differentiate into mature macrophages, thereby inducing pro-tumorigenic immunity. A critical factor regulating this differentiation is activation of SREBP2-a well-known transcription factor participating in tumorigenesis progression-through unknown cellular mechanisms. Here, we show that hypoxia-induced Golgi disassembly and Golgi-ER fusion in monocytic myeloid cells result in nuclear translocation and activation of SREBP2 in a SCAP-independent manner.

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The nuclear receptor co-repressor (NCoR) complex mediates transcriptional repression dependent on histone deacetylation by histone deacetylase 3 (HDAC3) as a component of the complex. Unexpectedly, we found that signaling by the receptor activator of nuclear factor κB (RANK) converts the NCoR/HDAC3 co-repressor complex to a co-activator of AP-1 and NF-κB target genes that are required for mouse osteoclast differentiation. Accordingly, the dominant function of NCoR/HDAC3 complexes in response to RANK signaling is to activate, rather than repress, gene expression.

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Article Synopsis
  • Iron metabolism plays a significant role in the development of obesity, particularly in how it regulates the differentiation of fat cells (adipocytes).
  • The study reveals that iron is crucial during the early stages of adipocyte differentiation, as its deficiency impairs the process by affecting the epigenetic marks of key genes involved in this differentiation, including Pparg.
  • Key enzymes that demethylate DNA and histones, such as Jumonji Domain-Containing 1A and Ten-Eleven Translocation 2, are identified as important for iron-dependent adipocyte differentiation, highlighting the complex relationship between iron availability and gene expression in fat cell development.
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While epigenetic modifications of DNA and histones play main roles in gene transcription regulation, recently discovered post-transcriptional RNA modifications, known as epitranscriptomic modifications, have been found to have a profound impact on gene expression by regulating RNA stability, localization and decoding efficiency. Importantly, genetic variations or environmental perturbations of epitranscriptome modifiers (that is, writers, erasers and readers) are associated with obesity and metabolic diseases, such as type 2 diabetes. The epitranscriptome is closely coupled to epigenetic signalling, adding complexity to our understanding of gene expression in both health and disease.

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Protein kinase A promotes beige adipogenesis downstream from β-adrenergic receptor signaling by phosphorylating proteins, including histone H3 lysine 9 (H3K9) demethylase JMJD1A. To ensure homeostasis, this process needs to be reversible however, this step is not well understood. We show that myosin phosphatase target subunit 1- protein phosphatase 1β (MYPT1-PP1β) phosphatase activity is inhibited via PKA-dependent phosphorylation, which increases phosphorylated JMJD1A and beige adipogenesis.

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Ribosome biogenesis is an energetically expensive program that is dictated by nutrient availability. Here we report that nutrient deprivation severely impairs precursor ribosomal RNA (pre-rRNA) processing and leads to the accumulation of unprocessed rRNAs. Upon nutrient restoration, pre-rRNAs stored under starvation are processed into mature rRNAs that are utilized for ribosome biogenesis.

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Adipocytes play an essential role in the maintenance of whole-body energy homeostasis. White adipocytes regulate energy storage, whereas brown and beige adipocytes regulate energy expenditure and heat production. De novo production of adipocytes (i.

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Ballooning degeneration of hepatocytes is a major distinguishing histological feature of non-alcoholic steatosis (NASH) progression that can lead to cirrhosis and hepatocellular carcinoma (HCC). In this study, we evaluated the effect of the selective PPARα modulator (SPPARMα) pemafibrate (Pema) and sodium-glucose cotransporter 2 (SGLT2) inhibitor tofogliflozin (Tofo) combination treatment on pathological progression in the liver of a mouse model of NASH (STAM) at two time points (onset of NASH progression and HCC survival). At both time points, the Pema and Tofo combination treatment significantly alleviated hyperglycemia and hypertriglyceridemia.

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Brown adipose tissue (BAT) is important for thermoregulation via uncoupling of oxidative phosphorylation. In addition to BAT-driven thermogenesis, mammals use induced browning of subcutaneous white adipose tissue (scWAT) as a mechanism to cope with chronic cold stress. Under acute cold stress in mammals, JMJD1A, a histone H3 lysine 9 (H3K9) demethylase, upregulates thermogenic genes via β-adrenergic signaling in BAT through higher-order chromatin structural changes that occur independent of histone demethylase activity.

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Enhancer activation is essential for cell-type specific gene expression during cellular differentiation, however, how enhancers transition from a hypoacetylated "primed" state to a hyperacetylated-active state is incompletely understood. Here, we show SET domain-containing 5 (SETD5) forms a complex with NCoR-HDAC3 co-repressor that prevents histone acetylation of enhancers for two master adipogenic regulatory genes Cebpa and Pparg early during adipogenesis. The loss of SETD5 from the complex is followed by enhancer hyperacetylation.

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Derlin family members (Derlins) are primarily known as components of the endoplasmic reticulum-associated degradation pathway that eliminates misfolded proteins. Here we report a function of Derlins in the brain development. Deletion of or in the central nervous system of mice impaired postnatal brain development, particularly of the cerebellum and striatum, and induced motor control deficits.

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Article Synopsis
  • * Researchers developed a FRET-based biosensor to measure nuclear α-KG concentration, featuring specific protein domains that respond to α-KG levels.
  • * This biosensor successfully tracked changes in nuclear α-KG during adipocyte differentiation, showing its potential for real-time monitoring and understanding of epigenetic regulation.
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  • SETDB1 is a lysine methyltransferase that methylates histone H3 at lysine 9, crucial for silencing retroviruses and developmental genes in human embryonic stem cells.
  • Recent findings indicate that while the ubiquitination of SETDB1 enhances its function in silencing retroviruses, its role in the epigenetic silencing of certain developmental genes is not fully understood.
  • The study reveals that a mutant form of SETDB1 (K885A), which is resistant to ubiquitination, can still repress adipogenic genes and limit pre-adipocyte differentiation, suggesting that SETDB1 has different mechanisms for gene repression—one that relies on ubiquitination and another that operates independently of its enzyme activity
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Importing necessary metabolites into the mitochondrial matrix is a crucial step of fuel choice during stress adaptation. Branched chain-amino acids (BCAAs) are essential amino acids needed for anabolic processes, but they are also imported into the mitochondria for catabolic reactions. What controls the distinct subcellular BCAA utilization during stress adaptation is insufficiently understood.

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Down syndrome critical region (DSCR)-1 functions as a feedback modulator for calcineurin-nuclear factor for activated T cell (NFAT) signals, which are crucial for cell proliferation and inflammation. Stable expression of DSCR-1 inhibits pathological angiogenesis and septic inflammation. DSCR-1 also plays a critical role in vascular wall remodeling associated with aneurysm development that occurs primarily in smooth muscle cells.

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Two large clinical studies showed that fenofibrate, a commonly used peroxisome proliferator-activated receptor α (PPARα) agonist, has protective effects against diabetic retinopathy. However, the underlying mechanism has not been clarified. We performed genome-wide analyses of gene expression and PPARα binding sites in vascular endothelial cells treated with the selective PPARα modulator pemafibrate and identified 221 target genes of PPARα including THBD, which encodes thrombomodulin (TM).

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Non-alcoholic steatohepatitis (NASH) is characterized by macrovesicular steatosis with ballooning degeneration of hepatocytes, diffused lobular inflammation, and fibrosis. PPAR ligands are promising therapeutic agents in NASH; accordingly, we evaluated the effects of the first clinically available selective PPARα modulator, pemafibrate. We found that pemafibrate improves F4/80-positive macrophage accumulation, ballooning degeneration of hepatocytes, and the non-alcoholic fatty liver disease (NAFLD) activity score without affecting triglyceride (TG) accumulation in the liver of a mouse model of NASH (STAM).

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Pemafibrate is the first clinically-available selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that has been shown to effectively improve hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) levels. Global gene expression analysis reveals that the activation of PPARα by pemafibrate induces fatty acid (FA) uptake, binding, and mitochondrial or peroxisomal oxidation as well as ketogenesis in mouse liver. Pemafibrate most profoundly induces and , which regulate the rate-limiting step of ketogenesis and glucose oxidation, respectively, compared to other fatty acid metabolic genes in human hepatocytes.

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Tolerance to severe tumor microenvironments, including hypoxia and nutrient starvation, is a common feature of aggressive cancer cells and can be targeted. However, metabolic alterations that support cancer cells upon nutrient starvation are not well understood. Here, by comprehensive metabolome analyses, we show that glutamine deprivation leads to phosphoethanolamine (PEtn) accumulation in cancer cells via the downregulation of PEtn cytidylyltransferase (PCYT2), a rate-limiting enzyme of phosphatidylethanolamine biosynthesis.

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