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城島　啓佑 (ジヨウジマ　ケイスケ)

薬学研究院　創薬科学部門　生体機能科学分野助教

研究者基本情報

■ 学位
  • 薬科学博士, 北海道大学, 2024年03月
■ URL
researchmap URLホームページURL■ ID 各種
研究者番号
  • 81003887
ORCID IDJ-Global ID■ 研究キーワード・分野
研究キーワード
  • ワックスエステル
  • 皮脂
  • 皮膚バリア
  • マイバム脂質
  • FADS3
  • スフィンガジエン
  • スフィンゴ脂質
研究分野
  • ライフサイエンス, 分子生物学
  • ライフサイエンス, 機能生物化学
  • ライフサイエンス, 薬系衛生、生物化学
■ 担当教育組織

経歴

■ 経歴
経歴
  • 2024年04月 - 現在
    北海道大学, 薬学部, 助教, 日本国
学歴
  • 2021年04月 - 2024年03月, 北海道大学, 大学院生命科学院, 生命科学専攻生命医薬科学コース 博士後期課程
  • 2019年04月 - 2021年03月, 北海道大学, 大学院生命科学院, 生命科学専攻生命医薬科学コース 博士前期過程, 日本国
  • 2015年04月 - 2019年03月, 北海道大学, 薬学部, 薬科学科, 日本国

研究活動情報

■ 受賞
  • 2026年06月, 日本脂質生化学会, 第68回 日本脂質生化学会 若手優秀発表賞
    脂腺（皮脂腺およびマイボーム腺）特異的脂質ワックスエステルの構造多様性と機能
    城島啓佑;栗林夏鈴;水野佑香;山本萌恵;武田美礼;寺井麻紀子;木原章雄
■ 論文
  • Time-dependent changes in meibum lipid composition and progression of dry eye following disruption of the fatty acid elongase Elovl1
    Himari Tada; Keisuke Jojima; Taiga Hiranuma; Takayuki Sassa; Akio Kihara
    Journal of Biological Chemistry, 2026年03月, ［査読有り］
    研究論文（学術雑誌）
  • Detailed Composition of Wax Esters in Mouse Sebum and the Involvement of FAR2 and AWAT2
    Karin Kuribayashi; Keisuke Jojima; Moe Yamamoto; Mirei Takeda; Akio Kihara
    iScience, 114836, 114836, Elsevier BV, 2026年01月, ［査読有り］
    研究論文（学術雑誌）
  • Comprehensive lipid analysis of human meibum and tears
    Makiko Terai; Keisuke Jojima; Megumi Ogawa-Sawai; Akio Kihara
    Scientific Reports, 15, 1, Springer Science and Business Media LLC, 2025年10月30日, ［査読有り］, ［筆頭著者］
    研究論文（学術雑誌）
  • Lipase M Is Essential for Skin Barrier Function in Mice
    Hong‐Ming Zhou; Jinan Li; Shaohui Liu; Miguel Barriera Diaz; Qun Wang; Emma H. Doud; Whitney Smith‐Kinnaman; Derrick A. Gray; Sou Shirai; Keisuke Jojima; Akio Kihara; Bo Zhao; Matthew J. Turner
    Experimental Dermatology, 34, 7, Wiley, 2025年07月10日, ［査読有り］
    研究論文（学術雑誌）, ABSTRACT

    A functional skin barrier is essential for restricting water losses for terrestrial animals. The outermost layer of this barrier, the stratum corneum, consists of corneocytes (derived from terminally differentiated keratinocytes) coated with a protein‐rich envelope and a conjugated lipid‐rich envelope embedded in an organised hydrophobic intercellular lipid matrix. Gene mutations and environmental insults that affect corneocyte formation or the intercellular lipid matrix organisation cause skin barrier defects in mice and humans. Here we demonstrate mice homozygous for a loss‐of‐function mutation in the Lipm gene exhibit a diminished and discontinuous intercellular lipid matrix and a profound skin barrier defect associated with neonatal lethality. These findings suggest the protein encoded by the Lipm gene, lipase M (LIPM), is essential for skin barrier function by impacting intercellular lipid matrix organisation in the stratum corneum.
  • The First Reported Japanese Case of PNPLA1‐Nonsyndromic Epidermal Differentiation Disorder (PNPLA1‐nEDD) Associated With an Unreported 92‐Base‐Pair Duplication Variant
    Shiori Kato; Takuya Takeichi; Keisuke Jojima; Maiko Kato; Michiya Omi; Kana Tanahashi; Atsushi Otsuka; Yoshinao Muro; Akio Kihara; Masashi Akiyama
    Experimental Dermatology, 34, 6, Wiley, 2025年06月23日, ［査読有り］
    研究論文（学術雑誌）, ABSTRACT

    Autosomal recessive congenital ichthyosis (ARCI) is a rare inherited skin disorder marked by generalised scaling and erythema. Very recently, diseases formerly diagnosed as ichthyosis, including ARCI, have been renamed nonsyndromic epidermal differentiation disorders (nEDDs). Although pathogenic variants in various genes, including PNPLA1, have been identified as causes, regional and ethnic differences exist in their prevalence. PNPLA1 encodes a unique transacylase essential for acylceramide synthesis, a critical component of the skin barrier. Here, we describe the first reported Japanese case of a PNPLA1‐related nonsyndromic epidermal differentiation disorder (PNPLA1‐nEDD) caused by a homozygous 92‐base‐pair duplication variant (c.36_127dup, p.Leu43Profs*46) in PNPLA1. Lipidomic analysis of the stratum corneum revealed marked reductions in ω‐O‐acylceramides and protein‐bound ceramides, alongside the accumulation of non‐acylated ceramides—indicating a failure in acylceramide synthesis. This ceramide profile supports the conclusion that the PNPLA1 duplication causes a loss of function. Our findings emphasise the importance of PNPLA1 in the genetic screening of nEDD cases in Japan, regardless of clinical subtype, due to the absence of genotype–phenotype correlations and to broad phenotypic variability.
  • Metabolism of sphingadiene and characterization of the sphingadiene-producing enzyme FADS3.
    Keisuke Jojima; Akio Kihara
    Biochimica et biophysica acta. Molecular and cell biology of lipids, 1868, 8, 159335, 159335, 2023年08月, ［査読有り］, ［筆頭著者］, ［国際誌］
    英語, 研究論文（学術雑誌）, Of the long-chain bases (LCBs) that comprise the ceramides (CERs) present in mammals, only 4,14-sphingadiene (sphingadiene; SPD) has a cis double bond (at C14). Because of this unique structure, the metabolism of SPD may differ from that of other LCBs, but whether this is the case remains unclear. FADS3 is responsible for introducing the cis double bond in SPD. However, the substrate specificity of FADS3 and cofactors involved in the FADS3-catalyzed reaction are also unknown. In the present study, a cell-based assay using a ceramide synthase inhibitor and an in vitro experiment showed that FADS3 is active toward sphingosine (SPH)-containing CERs (SPH-CERs) but not toward free SPH. FADS3 exhibits specificity with respect to the chain length of the SPH moiety of SPH-CERs (active toward C16-20), but not that of the fatty acid moiety. Furthermore, FADS3 is active toward straight-chain and iso-branched-chain SPH-containing CERs but not toward anteiso-branched forms. In addition to SPH-CERs, FADS3 also shows activity toward dihydrosphingosine-containing CERs, but this activity is approximately half of that toward SPH-CERs. It uses either NADH or NADPH as an electron donor, and the electron transfer is facilitated by cytochrome b5. The metabolic flow of SPD to sphingomyelin is predominant over that to glycosphingolipids. In the metabolic pathway from SPD to fatty acids, the chain length of the SPD is reduced by two carbons and the trans double bond at C4 is saturated. This study thus elucidates the enzymatic properties of FADS3 and the metabolism of SPD., 46764698
  • Bifunctional DEGS2 has higher hydroxylase activity toward substrates with very-long-chain fatty acids in the production of phytosphingosine ceramides.
    Ai Ota; Hiroya Morita; Tatsuro Naganuma; Masatoshi Miyamoto; Keisuke Jojima; Koki Nojiri; Junko Matsuda; Akio Kihara
    The Journal of biological chemistry, 299, 4, 104603, 104603, 2023年04月, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）, Phytosphingosine (PHS) is a sphingolipid component present mainly in epithelial tissues, including the epidermis and those lining the digestive tract. DEGS2 is a bifunctional enzyme that produces ceramides (CERs) containing PHS (PHS-CERs) via hydroxylation and sphingosine-CERs via desaturation, using dihydrosphingosine-CERs as substrates. Until now, the role of DEGS2 in permeability barrier functioning, its contribution to PHS-CER production, and the mechanism that differentiates between these two activities have been unknown. Here, we analyzed the barrier functioning of the epidermis, esophagus, and anterior stomach of Degs2 KO mice and found that there were no differences between Degs2 KO and WT mice, indicating normal permeability barriers in the KO mice. In the epidermis, esophagus, and anterior stomach of Degs2 KO mice, PHS-CER levels were greatly reduced relative to WT mice, but PHS-CERs were still present. We obtained similar results for DEGS2 KO human keratinocytes. These results indicate that although DEGS2 plays a major role in PHS-CER production, another synthesis pathway exists as well. Next, we examined the fatty acid (FA) composition of PHS-CERs in various mouse tissues and found that PHS-CER species containing very-long-chain FAs (≥C21) were more abundant than those containing long-chain FAs (C11-C20). A cell-based assay system revealed that the desaturase and hydroxylase activities of DEGS2 toward substrates with different FA chain lengths differed and that its hydroxylase activity was higher toward substrates containing very-long-chain FAs. Collectively, our findings contribute to the elucidation of the molecular mechanism of PHS-CER production.
  • Biosynthesis of the anti-lipid-microdomain sphingoid base 4,14-sphingadiene by the ceramide desaturase FADS3.
    Keisuke Jojima; Mai Edagawa; Megumi Sawai; Yusuke Ohno; Akio Kihara
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 34, 2, 3318, 3335, 2020年02月, ［査読有り］, ［筆頭著者］, ［国際誌］
    英語, 研究論文（学術雑誌）, Sphingolipids are multifunctional lipids. Among the sphingolipid-component sphingoid bases, 4,14-sphingadiene (SPD) is unique such that it has a cis double bond with a bent structure. Although SPD was discovered half a century ago, its tissue distribution, biosynthesis, and degradation remain poorly understood. Here, we established a specific and quantitative method for SPD measurement and found that SPD exists in a wide range of mammalian tissues. SPD was especially abundant in kidney, where the amount of SPD was ~2/3 of sphingosine, the most abundant sphingoid base in mammals. Although SPD is metabolized to ceramides and SPD 1-phosphate with almost the same efficiency as sphingosine, it is less susceptible to degradation by a cleavage reaction, at least in vitro. We identified the fatty acid desaturase family protein FADS3 as a ceramide desaturase that produces SPD ceramides by desaturating ceramides containing sphingosine. SPD sphingolipids were preferentially localized outside lipid microdomains, suggesting that SPD has different functions compared to other sphingoid bases in the formation of lipid microdomains. In summary, we revealed the biosynthesis and degradation pathways of SPD and its characteristic membrane localization. Our findings contribute to the elucidation of the molecular mechanism underlying the generation of sphingolipid diversity.
  • Structure-inspired design of a sphingolipid mimic sphingosine-1-phosphate receptor agonist from a naturally occurring sphingomyelin synthase inhibitor.
    Mahadeva M M Swamy; Yuta Murai; Yusuke Ohno; Keisuke Jojima; Akio Kihara; Susumu Mitsutake; Yasuyuki Igarashi; Jian Yu; Min Yao; Yoshiko Suga; Masaki Anetai; Kenji Monde
    Chemical communications (Cambridge, England), 54, 90, 12758, 12761, 2018年11月08日, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）, Ginkgolic acid obtained as a sphingomyelin synthase inhibitor from a plant extract library inspired the concept of sphingolipid mimics. Ginkgolic acid-derived N-acyl anilines and ginkgolic acid 2-phosphate (GA2P) respectively mimic ceramide and sphingosine 1-phosphate (S1P) in structure and function. The GA2P-induced phosphorylation of ERK and internalization of S1P receptor 1 (S1P1) indicated potent agonist activity. Docking studies revealed that GA2P adopts a similar binding conformation to the bound ligand ML5, which is a strong antagonist of S1P1.
■ その他活動・業績
■ 主な担当授業
  • 先端生物科学実験法Ⅰ, 2024年, 学士課程, 薬学部
■ 共同研究・競争的資金等の研究課題
  • アンチマイクロドメイン効果をもつスフィンガジエンの生理・病態機能の解明
    科学研究費助成事業
    2025年04月 - 2027年03月
    城島 啓佑
    日本学術振興会, 若手研究, 北海道大学, 25K18613
  • スフィンガジエンによるスフィンゴ脂質多様性創出機構の解明
    科学研究費助成事業
    2023年03月 - 2024年03月
    城島 啓佑
    予定通り脂肪酸不飽和化酵素FADS3の酵素学的解析とスフィンガジエン(SPD)の生理機能解明の2点について研究を行った。加えて，予定にはなかったSPDの代謝についての詳細な解析も行なった。
    FADS3の酵素学的解析について予定通り研究を遂行した。In vitroや細胞系での解析から，FADS3の基質が遊離のスフィンゴシンではなくセラミドであることを明らかにした。さらにセラミドの構成成分であるスフィンゴシンと脂肪酸の鎖長に対しての特異性を調べたところ，脂肪酸鎖長には基質特異性をもたない一方で，スフィンゴシン鎖長に対しては特異性をもつことを明らかにした。
    SPDの生理機能についても白色脂肪組織と腎臓の解析を予定通り行った。Fads3 KOマウスは通常状態では目立った表現型が見られないことから，高脂肪食負荷時の白色脂肪組織における機能を調べたが，野生型マウスと比較してKOマウスに大きな差異は見られなかった。続いて，腎機能障害を誘発することが知られるシスプラチンを投与したFads3 KOマウスの腎機能を生化学的解析により評価した。その結果，Fads3 KOマウスでは野生型と比較して腎機能が低下する傾向が見られ，SPDがシスプラチン誘発性の腎負荷を緩和する機能をもつことが示唆された。
    SPDの代謝について細胞のトレーサー実験から，SPDスフィンゴ糖脂質に代謝されづらいことが明らかとなった。
    本研究で明らかとなったFADS3の酵素学的特性は多彩で重要な機能を有するスフィンゴ脂質の構造多様性を生み出す分子的基盤の解明の一端を担うと考える。また，SPDの機能は今までほとんど明らかではなかったが，シスプラチン誘発性腎負荷によってFads3 KOマウスの腎臓機能低下が見られたことから，薬剤性腎不全とSPDの関連が示唆され，本研究結果は薬剤性腎不全の回避や治療に貢献する可能性があると考えられる。
    日本学術振興会, 特別研究員奨励費, 北海道大学, 研究代表者, 22KJ0087
  • スフィンガジエンによるスフィンゴ脂質多様性創出機構の解明
    北海道大学DX博士人材フェローシップ
    2021年10月 - 2022年03月
    北海道大学, 研究代表者