吉野 純 (ヨシノ ジュン)

Yoshino, Jun

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医学部 腎・代謝ナビゲーション医学寄附講座 (信濃町)

職名

特任准教授(有期)

 

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  • SIRT1 selectively exerts the metabolic protective effects of hepatocyte nicotinamide phosphoribosyltransferase

    Higgins C.B., Mayer A.L., Zhang Y., Franczyk M., Ballentine S., Yoshino J., DeBosch B.J.

    Nature Communications (Nature Communications)  13 ( 1 ) 1074 2022年12月

    ISSN  2041-1723

     概要を見る

    Calorie restriction abates aging and cardiometabolic disease by activating metabolic signaling pathways, including nicotinamide adenine dinucleotide (NAD+) biosynthesis and salvage. Nicotinamide phosphoribosyltransferase (NAMPT) is rate-limiting in NAD+ salvage, yet hepatocyte NAMPT actions during fasting and metabolic duress remain unclear. We demonstrate that hepatocyte NAMPT is upregulated in fasting mice, and in isolated hepatocytes subjected to nutrient withdrawal. Mice lacking hepatocyte NAMPT exhibit defective FGF21 activation and thermal regulation during fasting, and are sensitized to diet-induced glucose intolerance. Hepatocyte NAMPT overexpression induced FGF21 and adipose browning, improved glucose homeostasis, and attenuated dyslipidemia in obese mice. Hepatocyte SIRT1 deletion reversed hepatocyte NAMPT effects on dark-cycle thermogenesis, and hepatic FGF21 expression, but SIRT1 was dispensable for NAMPT insulin-sensitizing, anti-dyslipidemic, and light-cycle thermogenic effects. Hepatocyte NAMPT thus conveys key aspects of the fasting response, which selectively dissociate through hepatocyte SIRT1. Modulating hepatocyte NAD+ is thus a potential mechanism through which to attenuate fasting-responsive disease.

  • Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids

    Martino M.R., Gutiérrez-Aguilar M., Yiew N.K.H., Lutkewitte A.J., Singer J.M., McCommis K.S., Ferguson D., Liss K.H.H., Yoshino J., Renkemeyer M.K., Smith G.I., Cho K., Fletcher J.A., Klein S., Patti G.J., Burgess S.C., Finck B.N.

    Cell Reports (Cell Reports)  39 ( 4 ) 110733 2022年04月

    ISSN  2211-1247

     概要を見る

    Hepatic gluconeogenesis from amino acids contributes significantly to diabetic hyperglycemia, but the molecular mechanisms involved are incompletely understood. Alanine transaminases (ALT1 and ALT2) catalyze the interconversion of alanine and pyruvate, which is required for gluconeogenesis from alanine. We find that ALT2 is overexpressed in the liver of diet-induced obese and db/db mice and that the expression of the gene encoding ALT2 (GPT2) is downregulated following bariatric surgery in people with obesity. The increased hepatic expression of Gpt2 in db/db liver is mediated by activating transcription factor 4, an endoplasmic reticulum stress-activated transcription factor. Hepatocyte-specific knockout of Gpt2 attenuates incorporation of 13C-alanine into newly synthesized glucose by hepatocytes. In vivo Gpt2 knockdown or knockout in liver has no effect on glucose concentrations in lean mice, but Gpt2 suppression alleviates hyperglycemia in db/db mice. These data suggest that ALT2 plays a significant role in hepatic gluconeogenesis from amino acids in diabetes.

  • Intestinal Epithelial NAD<sup>+</sup>Biosynthesis Regulates GLP-1 Production and Postprandial Glucose Metabolism in Mice

    Nagahisa T., Yamaguchi S., Kosugi S., Homma K., Miyashita K., Irie J., Yoshino J., Itoh H.

    Endocrinology (United States) (Endocrinology (United States))  163 ( 4 )  2022年04月

    ISSN  00137227

     概要を見る

    Obesity is associated with perturbations in incretin production and whole-body glucose metabolism, but the precise underlying mechanism remains unclear. Here, we tested the hypothesis that nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular energy metabolism, plays a critical role in obesity-associated intestinal pathophysiology and systemic metabolic complications. To this end, we generated a novel mouse model, namely intestinal epithelial cell-specific Nampt knockout (INKO) mice. INKO mice displayed diminished glucagon-like peptide-1 (GLP-1) production, at least partly contributing to reduced early-phase insulin secretion and postprandial hyperglycemia. Mechanistically, loss of NAMPT attenuated the Wnt signaling pathway, resulting in insufficient GLP-1 production. We also found that diet-induced obese mice had compromised intestinal NAMPT-mediated NAD+ biosynthesis and Wnt signaling pathway, associated with impaired GLP-1 production and whole-body glucose metabolism, resembling the INKO mice. Finally, administration of a key NAD+ intermediate, nicotinamide mononucleotide (NMN), restored intestinal NAD+ levels and obesity-associated metabolic derangements, manifested by a decrease in ileal Proglucagon expression and GLP-1 production as well as postprandial hyperglycemia in INKO and diet-induced obese mice. Collectively, our study provides mechanistic and therapeutic insights into intestinal NAD+ biology related to obesity-associated dysregulation of GLP-1 production and postprandial hyperglycemia.

  • Circadian transcription factor NPAS2 and the NAD<sup>+</sup>-dependent deacetylase SIRT1 interact in the mouse nucleus accumbens and regulate reward

    Becker-Krail D.D., Parekh P.K., Ketchesin K.D., Yamaguchi S., Yoshino J., Hildebrand M.A., Dunham B., Ganapathiraju M.K., Logan R.W., McClung C.A.

    European Journal of Neuroscience (European Journal of Neuroscience)  55 ( 3 ) 675 - 693 2022年02月

    ISSN  0953816X

     概要を見る

    Substance use disorders are associated with disruptions to both circadian rhythms and cellular metabolic state. At the molecular level, the circadian molecular clock and cellular metabolic state may be interconnected through interactions with the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, sirtuin 1 (SIRT1). In the nucleus accumbens (NAc), a region important for reward, both SIRT1 and the circadian transcription factor neuronal PAS domain protein 2 (NPAS2) are highly enriched, and both are regulated by the metabolic cofactor NAD+. Substances of abuse, like cocaine, greatly disrupt cellular metabolism and promote oxidative stress; however, their effects on NAD+ in the brain remain unclear. Interestingly, cocaine also induces NAc expression of both NPAS2 and SIRT1, and both have independently been shown to regulate cocaine reward in mice. However, whether NPAS2 and SIRT1 interact in the NAc and/or whether together they regulate reward is unknown. Here, we demonstrate diurnal expression of Npas2, Sirt1 and NAD+ in the NAc, which is altered by cocaine-induced upregulation. Additionally, co-immunoprecipitation reveals NPAS2 and SIRT1 interact in the NAc, and cross-analysis of NPAS2 and SIRT1 chromatin immunoprecipitation sequencing reveals several reward-relevant and metabolic-related pathways enriched among shared gene targets. Notably, NAc-specific Npas2 knock-down or a functional Npas2 mutation in mice attenuates SIRT1-mediated increases in cocaine preference. Together, our data reveal an interaction between NPAS2 and SIRT1 in the NAc, which may serve to integrate cocaine's effects on circadian and metabolic factors, leading to regulation of drug reward.

  • Development of Alveolar Hemorrhage After Pfizer-BioNTech COVID-19 mRNA Vaccination in a Patient With Renal-Limited Anti-neutrophil Cytoplasmic Antibody-Associated Vasculitis: A Case Report

    Nishioka, K., Yamaguchi, S., Yasuda, I., Yoshimoto, N., Kojima, D., Kaneko, K., Aso, M., Nagasaka, T., Yoshida, E., Uchiyama, K., Tajima, T., Yoshino, J., Yoshida, T., Kanda, T. and Itoh, H.

    Front Med (Lausanne) 9   874831 2022年

    ISSN  2296-858X

     概要を見る

    Since the coronavirus disease 2019 (COVID-19) pandemic continues and a new variant of the virus has emerged, the COVID-19 vaccination campaign has progressed. Rare but severe adverse outcomes of COVID-19 vaccination such as anaphylaxis and myocarditis have begun to be noticed. Of note, several cases of new-onset antineutrophil cytoplasmic antibody-associated vasculitis (AAV) after COVID-19 mRNA vaccination have been reported. However, relapse of AAV in remission has not been recognized enough as an adverse outcome of COVID-19 vaccination. We report, to our knowledge, a first case of renal-limited AAV in remission using every 6-month rituximab administration that relapsed with pulmonary hemorrhage, but not glomerulonephritis, following the first dose of the Pfizer-BioNTech COVID-19 vaccine. The patient received the COVID-19 vaccine more than 6 months after the last dose of rituximab according to the recommendations. However, his CD19(+) B cell counts were found to be increased after admission, indicating that our case might have been prone to relapse after COVID-19 vaccination. Although our case cannot establish causality between AAV relapse and COVID-19 mRNA vaccination, a high level of clinical vigilance for relapse of AAV especially in patients undergoing rituximab maintenance therapy following COVID-19 vaccination should be maintained. Furthermore, elapsed time between rituximab administration and COVID-19 mRNA vaccination should be carefully adjusted based on AAV disease-activity.

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  • ACMSD: A Novel Target for Modulating NAD <sup>+</sup> Homeostasis

    Yoshino J.

    Trends in Endocrinology and Metabolism (Trends in Endocrinology and Metabolism)  30 ( 4 ) 229 - 232 2019年04月

    ISSN  10432760

     概要を見る

    NAD + has a pivotal role in regulating many biological processes. A recent study (Palzer et al., Cell Rep. 2018, 25;1359–1370) demonstrated that alpha-amino-beta-carboxy-muconate-semialdehyde decarboxylase (ACMSD) is a key regulator of NAD + metabolism and overexpression of human ACMSD leads to niacin dependency for NAD + biosynthesis in mice, providing important insights into human diseases associated with niacin/NAD + deficiency.

  • The role of breakfast in adipose tissue biology

    Yoshino J.

    Journal of Physiology (Journal of Physiology)  596 ( 4 ) 551 - 552 2018年02月

    ISSN  00223751

競争的研究費の研究課題 【 表示 / 非表示

  • 脂肪細胞NAD合成系を標的としたトランスレーショナル型研究の展開

    2021年04月
    -
    2024年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 吉野 純, 国際共同研究加速基金(帰国発展研究), 補助金,  研究代表者