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Invited Review : Metabolism of Very Long-Chain Fatty Acids: Genes and Pathophysiology
( Akio Kihara ),( Takayuki Sassa ) 한국응용약물학회 2014 Biomolecules & Therapeutics(구 응용약물학회지) Vol.22 No.2
Fatty acids (FAs) are highly diverse in terms of carbon (C) chain-length and number of double bonds. FAs with C>20 are calledvery long-chain fatty acids (VLCFAs). VLCFAs are found not only as constituents of cellular lipids such as sphingolipids and glycerophospholipidsbut also as precursors of lipid mediators. Our understanding on the function of VLCFAs is growing in parallelwith the identification of enzymes involved in VLCFA synthesis or degradation. A variety of inherited diseases, such as ichthyosis,macular degeneration, myopathy, mental retardation, and demyelination, are caused by mutations in the genes encoding VLCFAmetabolizing enzymes. In this review, we describe mammalian VLCFAs by highlighting their tissue distribution and metabolicpathways, and we discuss responsible genes and enzymes with reference to their roles in pathophysiology.
Formation of skin permeability barrier by diverse ceramides
( Akio Kihara ) 한국피부장벽학회 2023 한국피부장벽학회지 Vol.25 No.2
The permeability barrier in the stratum corneum of the skin (skin barrier) prevents the entry of foreign substances such as pathogens, allergens, and toxic compounds and water loss. Ceramides, lipids abundant in the stratum corneum, are essential for the formation of the skin barrier. Free ceramides (non-protein-bound ceramides) are components of the multilayered lipid structures (lipid lamellae) that exist between corneocytes. They are classified into non-acylated ceramides (conventional ceramides) and acylceramides. Acylceramides play an important role in the formation and maintenance of lipid lamellae. Protein-bound ceramides, which covalently bind to Cys residues of corneocyte surface proteins), are components of the corneocyte lipid envelope (CLE). We recently revealed that human stratum corneum contain 23 classes and 1,581 species of ceramides (18 classes/1,327 species of free ceramides and 5 classes/254 species of protein-bound ceramides) by LC-MS/MS analysis). Patients with atopic dermatitis have reduced amounts of ceramides and altered ceramide class composition. Mutations in genes involved in the synthesis of acylceramides and protein-bound ceramides cause congenital ichthyosis in humans and neonatal lethality due to skin barrier abnormalities in mice. We have identified many genes involved in acylceramide production (ELOVL1, CYP4F22, PNPLA1, ABHD5 and FATP4) and elucidated the details of the acylceramide synthesis pathway). In this presentation, I will describe the following four topics: 1. the diversity of ceramides in human stratum corneum, 2. ceramide analysis by LC-MS/MS, 3. skin disorders (atopic dermatitis and ichthyosis) caused by changes in ceramide composition, 4. the molecular mechanism of acylceramide production and its importance in skin barrier formation.
Sphingosine Kinase Assay System with Fluorescent Detection in High Performance Liquid Chromatography
You-Xun Jin,유환수,Akio Kihara,Chang-Hwan Choi,Seikwan Oh,문동철,Yasuyuki Igarashi,이용문 대한약학회 2006 Archives of Pharmacal Research Vol.29 No.11
Activation of Sphingosine kinase (Sphk) increases a bioactive lipid, sphingosine 1-phosphate (S1P) and has been observed in a variety of cancer cells. Therefore, inhibition of Sphk activity was an important target for the development of anticancer drugs. As a searching tool for Sphk inhibitor, we developed fluorescent Sphk activity assay combined with high performance liquid chromatography (HPLC). Previously we established murine teraticarcinoma mutant F9-12 cells which lack S1P lyase and stably express Sphk1. By using F9-12 cells, optimal assay conditions were established as follows; 100 μM of C17-Sph and 30 μg protein of F9-12 cells lysate in 20 min. Sphingosine analog C17-Sph was efficiently phosphorylated by Sphk activity (Km :67.08 μM, Vmax :1507.5 pmol/min/mg). New product C17-S1P was separated from S1P in reversedphase HPLC. In optimized conditions, 300 nM of phorbol 12-myristate 13-acetate (PMA) increased Sphk activity approximately twice while 20 μM of N,N-dimethylsphingosine (DMS) reduced 70% of Sphk activity in F9-12 cells lysate. In conclusion, we established non-radioactive but convenient Sphk assay system by using HPLC and F9-12 cells.
Sphingosine Kinase Assay System with Fluorescent Detection in High Performance Liquid Chromatography
Jin, You-Xun,Yoo, Hwan-Soo,Kihara, Akio,Choi, Chang-Hwan,Oh, Seik-Wan,Moon, Dong-Cheul,Igarashi, Yasuyuki,Lee, Yong-Moon The Pharmaceutical Society of Korea 2006 Archives of Pharmacal Research Vol.29 No.11
Activation of Sphingosine kinase (Sphk) increases a bioactive lipid, sphingosine 1-phosphate (S1P) and has been observed in a variety of cancer cells. Therefore, inhibition of Sphk activity was an important target for the development of anticancer drugs. As a searching tool for Sphk inhibitor, we developed fluorescent Sphk activity assay combined with high performance liquid chromatography (HPLC). Previously we established murine teraticarcinoma mutant F9-12 cells which lack S1P lyase and stably express Sphk1. By using F9-12 cells, optimal assay conditions were established as follows; $100\;{\mu}M\;of\;C_{17}-Sph\;and\;30\;{\mu}g$ protein of F9-12 cells lysate in 20 min. Sphingosine analog $C_{17}-Sph$ was efficiently phosphorylated by Sphk activity ($K_{m}:67.08\;{\mu}M,\;V_{max}\;:1507.5\;pmol/min/mg$). New product $C_{17}-S1P$ was separated from S1P in reversed-phase HPLC. In optimized conditions, 300 nM of phorbol 12-myristate 13-acetate (PMA) increased Sphk activity approximately twice while $20\;{\mu}M$ of N,N-dimethylsphingosine (DMS) reduced 70% of Sphk activity in F9-12 cells lysate. In conclusion, we established non-radioactive but convenient Sphk assay system by using HPLC and F9-12 cells.