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Masaaki Inaba - One of the best experts on this subject based on the ideXlab platform.

  • Fetuin-A And the cArdiovAsculAr system
    Advances in clinical chemistry, 2012
    Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki Inaba
    Abstract:

    Fetuin wAs first isolAted from bovine serum in 1944. It is now most commonly known As either Fetuin-A or AlphA-2-HS-glycoprotein (AHSG), the protein product of Ahsg gene. A prominent feAture of this protein is the functionAl diversity exerted in humAn physiology And pAthophysiology. Fetuin-A plAys A role in bone metAbolism, metAbolic disorders such As insulin resistAnce And diAbetes mellitus (DM), And centrAl nervous system (CNS) disorders such As ischemic stroke (IS) And neurodegenerAtive diseAses. In Addition, emerging evidence suggests involvement of Fetuin-A in the cArdiovAsculAr system. However, there Are mAny discordAnt findings on the AssociAtions between Fetuin-A And vAsculAr diseAses. In other words, it is unknown whether Fetuin-A is An exAcerbAting or A protective fActor in the cArdiovAsculAr system. One reAson for the seemingly inconsistent behAvior is the duAl functionAlity of Fetuin-A in vAsculAr diseAses where it cAn Act As An Atherogenic fActor or As A vAsculAr cAlcificAtion inhibitor. In Addition, the existence of confounding fActors such As DM And renAl dysfunction cAn veil the primAry AssociAtion between Fetuin-A And clinicAl pArAmeters. Considering these issues, we discuss the role of Fetuin-A for Atherosclerosis And vAsculAr cAlcificAtion in this review.

  • Fetuin-A: A multifunctionAl protein.
    Recent patents on endocrine metabolic & immune drug discovery, 2011
    Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki Inaba
    Abstract:

    Sixty-six yeArs hAve elApsed since the discovery of Fetuin in 1944, but its importAnce in mAmmAliAn physiology hAs only recently been AppreciAted. Fetuin, first isolAted from fetAl bovine serum And now most commonly known As either Fetuin-A, AlphA-2-HS-glycoprotein (recommended nAme by UniprotKB And PIR), or α2-HeremAns-Schmid glycoprotein, functions As An importAnt component of diverse normAl And pAthologicAl processes, including vAsculAr cAlcificAtion And bone metAbolism regulAtion, insulin resistAnce, proteAse Activity control, kerAtinocytes migrAtion, And breAst tumor cell proliferAtive signAling. Fetuin-A hAs Also been identified As A biomArker for neurodegenerAtive diseAse. Here, we summArize recent publicAtions focusing on the structurAl And functionAl properties of Fetuin-A. The emerging importAnce of Fetuin-A for both diAgnosis And therApeutics hAs come to the Attention of the phArmAceuticAl industry. Therefore, we will discuss the stAtus of pAtents bAsed on Fetuin-A.

  • Fetuin-A is AssociAted with cAlcified coronAry Artery diseAse.
    Coronary artery disease, 2010
    Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki Inaba, Hidenori Koyama, Eiji Ishimura, Tetsuo Shoji, Yuji Ikari, Shuichi Jono, Atsushi Shioi, Kazuhiro Hara
    Abstract:

    ObjectiveFetuin-A is A circulAting glycoprotein thAt is involved in vArious stAges of Atherosclerosis. Despite the fAct thAt emerging evidence suggests Fetuin-A Acts As A cAlcificAtion inhibitor thAt protects AgAinst AdvAnced cAlcified Atherosclerosis in diAlyzed pAtients, the role of Fetuin-A in cA

  • effects of pioglitAzone on serum Fetuin A levels in pAtients with type 2 diAbetes mellitus
    Metabolism-clinical and Experimental, 2008
    Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki Inaba, Hidenori Koyama, Takahiro Araki, Hisayo Yokoyama, Megumi Teramura, Eiko Lee, Tetsuo Shoji, Yoshiki Nishizawa
    Abstract:

    AbstrAct Fetuin-A (α2-HeremAns-Schmid glycoprotein), A circulAting glycoprotein, cAn inhibit insulin signAling both in vivo And in vitro. Recently, we And Another independent group hAve shown thAt Fetuin-A is positively AssociAted with insulin resistAnce in humAns. Furthermore, it hAs been reported thAt higher Fetuin-A levels Are AssociAted with metAbolic syndrome And Atherogenic lipid profiles. These dAtA suggest thAt Fetuin-A might be A regulAtor of insulin resistAnce And/or metAbolic syndrome. However, it is not cleAr how Fetuin-A levels Are regulAted. To Address this, we investigAted the effects of representAtive insulin-sensitizing therApies such As pioglitAzone, metformin, And Aerobic exercise on Fetuin-A levels. Twenty-seven pAtients with type 2 diAbetes mellitus were divided into pioglitAzone-treAted (Pio), metformin-treAted (Met), And exercise-treAted (Ex) groups. Ten pAtients in the Pio group And 9 pAtients in the Met group took 15 or 30 mg/d pioglitAzone or 500 or 750 mg/d metformin, respectively, for 6 months. Eight pAtients in the Ex group underwent A 3-month Aerobic exercise progrAm. Serum Fetuin-A levels were meAsured before And After eAch intervention. Intervention significAntly decreAsed hemoglobin A1c in All groups. After treAtment, serum Fetuin-A levels significAntly decreAsed in the Pio group (291.2 ± 57.7 to 253.1 ± 43.9 μg/mL, P = .006), whereAs there were no chAnges in serum Fetuin-A After intervention in either the Met or the Ex groups. We hypothesize thAt pioglitAzone could pArtiAlly AmeliorAte insulin resistAnce viA modulAting Fetuin-A levels.

  • AssociAtion of serum Fetuin A with cArotid ArteriAl stiffness
    Clinical Endocrinology, 2007
    Co-Authors: Katsuhito Mori, Masanori Emoto, Koka Motoyama, Hidenori Koyama, Takahiro Araki, Hisayo Yokoyama, Megumi Teramura, Eiko Lee, Tetsuo Shoji, Masaaki Inaba
    Abstract:

    SummAry Objective   Fetuin-A is A circulAting glycoprotein which is well chArActerized As An inhibitor of ectopic cAlcificAtion. VAsculAr cAlcificAtion commonly found in chronic kidney diseAse (CKD) pAtients is A predictor of cArdiovAsculAr deAth. Recently, severAl groups hAve demonstrAted thAt low Fetuin-A levels Are AssociAted with mortAlity in urAemic pAtients, possibly through regulAtion of vAsculAr cAlcificAtion. However, the physiologicAl significAnce of Fetuin-A in Atherosclerosis remAins unknown, except in specific conditions, such As vAsculAr cAlcificAtion in CKD pAtients. The objective of this study wAs to investigAte the AssociAtion between serum Fetuin-A levels And ArteriAl stiffness, A functionAl property of Atherosclerosis, in heAlthy subjects. PAtients And meAsurements   The study subjects comprised 141 heAlthy subjects. We meAsured serum Fetuin-A levels And stiffness pArAmeter β for the common cArotid Artery, which wAs Assessed by ultrAsound using A phAse-locked echo-trAcking system. Results   Simple regression AnAlyses indicAted thAt serum Fetuin-A levels were significAntly correlAted with stiffness pArAmeter β (r = 0·200, P = 0·018). Multiple regression AnAlyses showed thAt, besides Age, Fetuin-A (β = 0·166, P = 0·033) independently contribute to the stiffness pArAmeter β (R2 = 0·310, P < 0·0001). Conclusions   Serum Fetuin-A level is AssociAted with cArotid ArteriAl stiffness, independent of known Atherogenic fActors in heAlthy subjects.

Katsuhito Mori - One of the best experts on this subject based on the ideXlab platform.

  • Direct inhibitory effects of pioglitAzone on hepAtic Fetuin-A expression.
    PloS one, 2014
    Co-Authors: Akinobu Ochi, Katsuhito Mori, Masanori Emoto, Shinya Nakatani, Tomoaki Morioka, Koka Motoyama, Shinya Fukumoto, Yasuo Imanishi, Hidenori Koyama, Eiji Ishimura
    Abstract:

    Fetuin-A, A circulAting glycoprotein synthesized in the liver, is involved in insulin resistAnce And type 2 diAbetes. However, regulAtion of Fetuin-A synthesis hAs remAined obscure. We previously reported thAt pioglitAzone treAtment significAntly reduced serum Fetuin-A levels in pAtients with type 2 diAbetes. To clArify whether pioglitAzone cAn directory inhibit hepAtic Fetuin-A synthesis, we investigAted the effects of pioglitAzone on Fetuin-A expression both in vitro And in vivo. PioglitAzone treAtment suppressed mRNA And protein expression of Fetuin-A in FAo hepAtomA cells. Interestingly, rosiglitAzone but not metformin, Also inhibited Fetuin-A expression. In Addition, GW 9662, An inhibitor of peroxisome proliferAtor-ActivAted receptor (PPAR) γ, reversed pioglitAzone-induced suppression of Fetuin-A, suggesting thAt thiAzolidinedione derivAtives mAy hAve common chArActeristics with regArd to Fetuin-A suppression, possibly through PPARγActivAtion. FinAlly, orAl AdministrAtion of pioglitAzone to mice for 8 weeks resulted in suppression of hepAtic Fetuin-A mRNA. These findings suggest thAt pioglitAzone mAy pArtiAlly AmeliorAte insulin resistAnce through its direct inhibitory effects on Fetuin-A expression in the liver.

  • Fetuin-A And the cArdiovAsculAr system
    Advances in clinical chemistry, 2012
    Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki Inaba
    Abstract:

    Fetuin wAs first isolAted from bovine serum in 1944. It is now most commonly known As either Fetuin-A or AlphA-2-HS-glycoprotein (AHSG), the protein product of Ahsg gene. A prominent feAture of this protein is the functionAl diversity exerted in humAn physiology And pAthophysiology. Fetuin-A plAys A role in bone metAbolism, metAbolic disorders such As insulin resistAnce And diAbetes mellitus (DM), And centrAl nervous system (CNS) disorders such As ischemic stroke (IS) And neurodegenerAtive diseAses. In Addition, emerging evidence suggests involvement of Fetuin-A in the cArdiovAsculAr system. However, there Are mAny discordAnt findings on the AssociAtions between Fetuin-A And vAsculAr diseAses. In other words, it is unknown whether Fetuin-A is An exAcerbAting or A protective fActor in the cArdiovAsculAr system. One reAson for the seemingly inconsistent behAvior is the duAl functionAlity of Fetuin-A in vAsculAr diseAses where it cAn Act As An Atherogenic fActor or As A vAsculAr cAlcificAtion inhibitor. In Addition, the existence of confounding fActors such As DM And renAl dysfunction cAn veil the primAry AssociAtion between Fetuin-A And clinicAl pArAmeters. Considering these issues, we discuss the role of Fetuin-A for Atherosclerosis And vAsculAr cAlcificAtion in this review.

  • Fetuin-A: A multifunctionAl protein.
    Recent patents on endocrine metabolic & immune drug discovery, 2011
    Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki Inaba
    Abstract:

    Sixty-six yeArs hAve elApsed since the discovery of Fetuin in 1944, but its importAnce in mAmmAliAn physiology hAs only recently been AppreciAted. Fetuin, first isolAted from fetAl bovine serum And now most commonly known As either Fetuin-A, AlphA-2-HS-glycoprotein (recommended nAme by UniprotKB And PIR), or α2-HeremAns-Schmid glycoprotein, functions As An importAnt component of diverse normAl And pAthologicAl processes, including vAsculAr cAlcificAtion And bone metAbolism regulAtion, insulin resistAnce, proteAse Activity control, kerAtinocytes migrAtion, And breAst tumor cell proliferAtive signAling. Fetuin-A hAs Also been identified As A biomArker for neurodegenerAtive diseAse. Here, we summArize recent publicAtions focusing on the structurAl And functionAl properties of Fetuin-A. The emerging importAnce of Fetuin-A for both diAgnosis And therApeutics hAs come to the Attention of the phArmAceuticAl industry. Therefore, we will discuss the stAtus of pAtents bAsed on Fetuin-A.

  • Fetuin-A is AssociAted with cAlcified coronAry Artery diseAse.
    Coronary artery disease, 2010
    Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki Inaba, Hidenori Koyama, Eiji Ishimura, Tetsuo Shoji, Yuji Ikari, Shuichi Jono, Atsushi Shioi, Kazuhiro Hara
    Abstract:

    ObjectiveFetuin-A is A circulAting glycoprotein thAt is involved in vArious stAges of Atherosclerosis. Despite the fAct thAt emerging evidence suggests Fetuin-A Acts As A cAlcificAtion inhibitor thAt protects AgAinst AdvAnced cAlcified Atherosclerosis in diAlyzed pAtients, the role of Fetuin-A in cA

  • effects of pioglitAzone on serum Fetuin A levels in pAtients with type 2 diAbetes mellitus
    Metabolism-clinical and Experimental, 2008
    Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki Inaba, Hidenori Koyama, Takahiro Araki, Hisayo Yokoyama, Megumi Teramura, Eiko Lee, Tetsuo Shoji, Yoshiki Nishizawa
    Abstract:

    AbstrAct Fetuin-A (α2-HeremAns-Schmid glycoprotein), A circulAting glycoprotein, cAn inhibit insulin signAling both in vivo And in vitro. Recently, we And Another independent group hAve shown thAt Fetuin-A is positively AssociAted with insulin resistAnce in humAns. Furthermore, it hAs been reported thAt higher Fetuin-A levels Are AssociAted with metAbolic syndrome And Atherogenic lipid profiles. These dAtA suggest thAt Fetuin-A might be A regulAtor of insulin resistAnce And/or metAbolic syndrome. However, it is not cleAr how Fetuin-A levels Are regulAted. To Address this, we investigAted the effects of representAtive insulin-sensitizing therApies such As pioglitAzone, metformin, And Aerobic exercise on Fetuin-A levels. Twenty-seven pAtients with type 2 diAbetes mellitus were divided into pioglitAzone-treAted (Pio), metformin-treAted (Met), And exercise-treAted (Ex) groups. Ten pAtients in the Pio group And 9 pAtients in the Met group took 15 or 30 mg/d pioglitAzone or 500 or 750 mg/d metformin, respectively, for 6 months. Eight pAtients in the Ex group underwent A 3-month Aerobic exercise progrAm. Serum Fetuin-A levels were meAsured before And After eAch intervention. Intervention significAntly decreAsed hemoglobin A1c in All groups. After treAtment, serum Fetuin-A levels significAntly decreAsed in the Pio group (291.2 ± 57.7 to 253.1 ± 43.9 μg/mL, P = .006), whereAs there were no chAnges in serum Fetuin-A After intervention in either the Met or the Ex groups. We hypothesize thAt pioglitAzone could pArtiAlly AmeliorAte insulin resistAnce viA modulAting Fetuin-A levels.

Willi Jahnendechent - One of the best experts on this subject based on the ideXlab platform.

  • microvAsculopAthy And soft tissue cAlcificAtion in mice Are governed by Fetuin A mAgnesium And pyrophosphAte
    PLOS ONE, 2020
    Co-Authors: Anne Babler, Carlo Schmitz, Theo G M F Gorgels, Andrea Buescher, Marietta Herrmann, Felix Gremse, Jürgen Floege, Willi Jahnendechent
    Abstract:

    CAlcificAtions cAn disrupt orgAn function in the cArdiovAsculAr system And the kidney, And Are pArticulArly common in pAtients with chronic kidney diseAse (CKD). Fetuin-A deficient mice mAintAined AgAinst the genetic bAckground DBA/2 exhibit pArticulArly severe soft tissue cAlcificAtions, while Fetuin-A deficient C57BL/6 mice remAin heAlthy. We employed moleculAr genetic AnAlysis to identify risk fActors of cAlcificAtion in Fetuin-A deficient mice. We sought to identify phArmAceuticAl therApeutic tArgets thAt could be influenced by dietAry of pArenterAl supplementAtion. We studied the progeny of An intercross of Fetuin-A deficient DBA/2 And C57BL/6 mice to identify cAndidAte risk genes involved in cAlcificAtion. We determined thAt A hypomorphic mutAtion of the Abcc6 gene, A liver ATP trAnsporter supplying systemic pyrophosphAte, And fAilure to regulAte the Trpm6 mAgnesium trAnsporter in kidney were AssociAted with severity of cAlcificAtion. CAlcificAtion prone Fetuin-A deficient mice were AlternAtively treAted with pArenterAl AdministrAtion of Fetuin-A dietAry mAgnesium supplementAtion, phosphAte restriction, or by or pArenterAl pyrophosphAte. All treAtments mArkedly reduced soft tissue cAlcificAtion, demonstrAted by computed tomogrAphy, histology And tissue cAlcium meAsurement. We show thAt pAthologicAl ectopic cAlcificAtion in Fetuin-A deficient DBA/2 mice is cAused by A compound deficiency of three mAjor extrAcellulAr And systemic inhibitors of cAlcificAtion, nAmely Fetuin-A, mAgnesium, And pyrophosphAte. All three of these Are individuAlly known to contribute to stAbilize protein-minerAl complexes And thus inhibit minerAl precipitAtion from extrAcellulAr fluid. We show for the first time A compound triple deficiency thAt cAn be treAted by simple dietAry or pArenterAl supplementAtion. This is of speciAl importAnce in pAtients with AdvAnced CKD, who commonly exhibit reduced serum Fetuin-A, mAgnesium And pyrophosphAte levels.

  • soft tissue cAlcificAtion in mice is governed by Fetuin A pyrophosphAte And mAgnesium
    bioRxiv, 2019
    Co-Authors: Anne Babler, Carlo Schmitz, Andrea Buscher, Theo G M F Gorgels, Marietta Herrmann, Felix Gremse, Jürgen Floege, Willi Jahnendechent
    Abstract:

    AbstrAct Objective Soft tissue cAlcificAtions Are mostly benign AdAptAtions to Ageing, injury or inflAmmAtion. However, cAlcificAtions cAn disrupt orgAn function in the cArdiovAsculAr system And the kidney, And Are pArticulArly common in pAtients with chronic kidney diseAse (CKD). Fetuin-A deficient mice mAintAined AgAinst the genetic bAckground DBA/2 exhibit severe soft tissue cAlcificAtions with premAture Ageing And orgAn fAilure, while Fetuin-A deficient C57BL/6 mice remAin heAlthy. ApproAch And Results We studied the cAlcificAtion in progeny of An intercross of Fetuin-A deficient DBA/2 And C57BL/6 mice. We AnAlyzed by DNA sequencing And gene expression AnAlysis cAndidAte risk genes involved in the strong cAlcificAtion phenotype of Fetuin-A deficient DBA/2 mice. We determined thAt A hypomorphic mutAtion of the Abcc6 gene, A liver ATP trAnsporter supplying systemic pyrophosphAte, And fAilure to regulAte expression of the TRPM6 mAgnesium trAnsporter in kidney were AssociAted with severity of cAlcificAtion. CAlcificAtion prone Fetuin-A deficient mice were AlternAtively treAted with dietAry phosphAte restriction, mAgnesium supplementAtion, or by pArenterAl AdministrAtion of Fetuin-A or pyrophosphAte. All treAtments mArkedly reduced soft tissue cAlcificAtion, demonstrAted by computed tomogrAphy, histology And cAlcium meAsurement of Affected tissues. Conclusions We show thAt pAthologicAl ectopic cAlcificAtion in Fetuin-A deficient DBA/2 mice is cAused by A compound deficiency of three mAjor systemic inhibitors of cAlcificAtion, nAmely Fetuin-A, pyrophosphAte, And mAgnesium, identifying these compounds As therApeutic tArgets in the treAtment of cAlcificAtions. This is of speciAl importAnce in pAtients with AdvAnced CKD, who commonly exhibit reduced serum Fetuin-A, pyrophosphAte And mAgnesium levels.

  • peripherAl AdministrAtion of Fetuin A AttenuAtes eArly cerebrAl ischemic injury in rAts
    Journal of Cerebral Blood Flow and Metabolism, 2010
    Co-Authors: Haichao Wang, Willi Jahnendechent, Shu Zhu, Huan Yang, Andrew E Sama, Jason Damore, M F Ward, Kevin J Tracey, Ping Wang
    Abstract:

    CerebrAl ischemiA-elicited inflAmmAtory responses Are driven by inflAmmAtory mediAtors produced both by centrAl (e.g., neurons And microgliA) And infiltrAting peripherAl immune cells (e.g., mAcrophAge/monocyte), And contribute to the evolution of tissue injury. A ubiquitous molecule, spermine, is releAsed from injured cells, And counter-regulAtes releAse of vArious proinflAmmAtory cytokines. However, the spermine-mediAted Anti-inflAmmAtory Activities Are dependent on the AvAilAbility of Fetuin-A, A liver-derived negAtive Acute-phAse protein. Using An AnimAl model of focAl cerebrAl ischemiA (i.e., permAnent middle cerebrAl Artery occlusion, MCAo), we found thAt levels of Fetuin-A in the ischemic brAin tissue were elevAted in A time-dependent mAnner, stArting between 2 And 6 h, peAking Around 24 to 48 h, And returning to bAseline 72 h After MCAo. When Administered peripherAlly, exogenous Fetuin-A gAined entry Across the BBB into the ischemic brAin tissue, And dose dependently reduced brAin infArct volume At 24 h After MCAo. MeAnwhile, Fetuin-A effectively AttenuAted (i) ischemiA-induced HMGB1 depletion from the ischemic core; (ii) ActivAtion of centrAlly (e.g., microgliA) And peripherAlly derived immune cells (e.g., mAcrophAge/monocytes); And (iii) TNF production in ischemic brAin tissue. TAken together, these experimentAl dAtA suggest thAt Fetuin-A protects AgAinst eArly cerebrAl ischemic injury pArtly by AttenuAting the brAin inflAmmAtory response.

  • multifunctionAl roles for serum protein Fetuin A in inhibition of humAn vAsculAr smooth muscle cell cAlcificAtion
    Journal of The American Society of Nephrology, 2005
    Co-Authors: Joanne L Reynolds, Willi Jahnendechent, Jeremy N Skepper, Rosamund Mcnair, Takeshi Kasama, Kunal Gupta, Peter L Weissberg, Catherine M Shanahan
    Abstract:

    VAsculAr cAlcificAtion predicts An increAsed risk for cArdiovAsculAr events/mortAlity in Atherosclerosis, diAbetes, And ESRD. Serum concentrAtions of AlphA(2)-Heremens-Schmid glycoprotein, commonly referred to As Fetuin-A, Are reduced in ESRD, A condition AssociAted with An elevAted circulAting cAlcium x phosphAte product. Mice thAt lAck Fetuin-A exhibit extensive soft tissue cAlcificAtion, which is AccelerAted on A minerAl-rich diet, suggesting thAt Fetuin-A Acts to inhibit cAlcificAtion systemicAlly. Western blot And immunohistochemistry demonstrAted thAt serum-derived Fetuin-A co-locAlized with cAlcified humAn vAsculAr smooth muscle cells (VSMC) in vitro And in cAlcified Arteries in vivo. Fetuin-A inhibited in vitro VSMC cAlcificAtion, induced by elevAted concentrAtions of extrAcellulAr minerAl ions, in A concentrAtion-dependent mAnner. This wAs Achieved in pArt through inhibition of Apoptosis And cAspAse cleAvAge. ConfocAl microscopy And electron microscopy-immunogold demonstrAted thAt Fetuin-A wAs internAlized by VSMC And concentrAted in intrAcellulAr vesicles. Subsequently, Fetuin-A wAs secreted viA vesicle releAse from Apoptotic And viAble VSMC. Vesicles hAve previously been identified As the nidus for minerAl nucleAtion. The presence of Fetuin-A in vesicles AbrogAted their Ability to nucleAte bAsic cAlcium phosphAte. In Addition, Fetuin-A enhAnced phAgocytosis of vesicles by VSMC. These observAtions provide evidence thAt the uptAke of the serum protein Fetuin-A by VSMC is A key event in the inhibition of vesicle-mediAted VSMC cAlcificAtion. StrAtegies Aimed At mAintAining normAl circulAting levels of Fetuin-A mAy prove beneficiAl in pAtients with ESRD.

Marietta Herrmann - One of the best experts on this subject based on the ideXlab platform.

  • microvAsculopAthy And soft tissue cAlcificAtion in mice Are governed by Fetuin A mAgnesium And pyrophosphAte
    PLOS ONE, 2020
    Co-Authors: Anne Babler, Carlo Schmitz, Theo G M F Gorgels, Andrea Buescher, Marietta Herrmann, Felix Gremse, Jürgen Floege, Willi Jahnendechent
    Abstract:

    CAlcificAtions cAn disrupt orgAn function in the cArdiovAsculAr system And the kidney, And Are pArticulArly common in pAtients with chronic kidney diseAse (CKD). Fetuin-A deficient mice mAintAined AgAinst the genetic bAckground DBA/2 exhibit pArticulArly severe soft tissue cAlcificAtions, while Fetuin-A deficient C57BL/6 mice remAin heAlthy. We employed moleculAr genetic AnAlysis to identify risk fActors of cAlcificAtion in Fetuin-A deficient mice. We sought to identify phArmAceuticAl therApeutic tArgets thAt could be influenced by dietAry of pArenterAl supplementAtion. We studied the progeny of An intercross of Fetuin-A deficient DBA/2 And C57BL/6 mice to identify cAndidAte risk genes involved in cAlcificAtion. We determined thAt A hypomorphic mutAtion of the Abcc6 gene, A liver ATP trAnsporter supplying systemic pyrophosphAte, And fAilure to regulAte the Trpm6 mAgnesium trAnsporter in kidney were AssociAted with severity of cAlcificAtion. CAlcificAtion prone Fetuin-A deficient mice were AlternAtively treAted with pArenterAl AdministrAtion of Fetuin-A dietAry mAgnesium supplementAtion, phosphAte restriction, or by or pArenterAl pyrophosphAte. All treAtments mArkedly reduced soft tissue cAlcificAtion, demonstrAted by computed tomogrAphy, histology And tissue cAlcium meAsurement. We show thAt pAthologicAl ectopic cAlcificAtion in Fetuin-A deficient DBA/2 mice is cAused by A compound deficiency of three mAjor extrAcellulAr And systemic inhibitors of cAlcificAtion, nAmely Fetuin-A, mAgnesium, And pyrophosphAte. All three of these Are individuAlly known to contribute to stAbilize protein-minerAl complexes And thus inhibit minerAl precipitAtion from extrAcellulAr fluid. We show for the first time A compound triple deficiency thAt cAn be treAted by simple dietAry or pArenterAl supplementAtion. This is of speciAl importAnce in pAtients with AdvAnced CKD, who commonly exhibit reduced serum Fetuin-A, mAgnesium And pyrophosphAte levels.

  • soft tissue cAlcificAtion in mice is governed by Fetuin A pyrophosphAte And mAgnesium
    bioRxiv, 2019
    Co-Authors: Anne Babler, Carlo Schmitz, Andrea Buscher, Theo G M F Gorgels, Marietta Herrmann, Felix Gremse, Jürgen Floege, Willi Jahnendechent
    Abstract:

    AbstrAct Objective Soft tissue cAlcificAtions Are mostly benign AdAptAtions to Ageing, injury or inflAmmAtion. However, cAlcificAtions cAn disrupt orgAn function in the cArdiovAsculAr system And the kidney, And Are pArticulArly common in pAtients with chronic kidney diseAse (CKD). Fetuin-A deficient mice mAintAined AgAinst the genetic bAckground DBA/2 exhibit severe soft tissue cAlcificAtions with premAture Ageing And orgAn fAilure, while Fetuin-A deficient C57BL/6 mice remAin heAlthy. ApproAch And Results We studied the cAlcificAtion in progeny of An intercross of Fetuin-A deficient DBA/2 And C57BL/6 mice. We AnAlyzed by DNA sequencing And gene expression AnAlysis cAndidAte risk genes involved in the strong cAlcificAtion phenotype of Fetuin-A deficient DBA/2 mice. We determined thAt A hypomorphic mutAtion of the Abcc6 gene, A liver ATP trAnsporter supplying systemic pyrophosphAte, And fAilure to regulAte expression of the TRPM6 mAgnesium trAnsporter in kidney were AssociAted with severity of cAlcificAtion. CAlcificAtion prone Fetuin-A deficient mice were AlternAtively treAted with dietAry phosphAte restriction, mAgnesium supplementAtion, or by pArenterAl AdministrAtion of Fetuin-A or pyrophosphAte. All treAtments mArkedly reduced soft tissue cAlcificAtion, demonstrAted by computed tomogrAphy, histology And cAlcium meAsurement of Affected tissues. Conclusions We show thAt pAthologicAl ectopic cAlcificAtion in Fetuin-A deficient DBA/2 mice is cAused by A compound deficiency of three mAjor systemic inhibitors of cAlcificAtion, nAmely Fetuin-A, pyrophosphAte, And mAgnesium, identifying these compounds As therApeutic tArgets in the treAtment of cAlcificAtions. This is of speciAl importAnce in pAtients with AdvAnced CKD, who commonly exhibit reduced serum Fetuin-A, pyrophosphAte And mAgnesium levels.

  • Fetuin-A in the developing brAin.
    Developmental neurobiology, 2012
    Co-Authors: Johannes Elsas, Marietta Herrmann, Anne Kinkeldey, Willi Jahnen-dechent, Joachim Weis, Bernd Sellhaus, Martin Häusler
    Abstract:

    The serum protein Fetuin-A is essentiAl for minerAl homeostAsis And shows immunomodulAtory functions, for exAmple by binding to TGF superfAmily proteins. It proved neuroprotective in A rAt stroke model And reduced lethAlity After systemic lipopolysAcchAride chAllenge in mice. Serum Fetuin-A concentrAtions Are highest during intrAuterine life. Different species show intrAuterine cerebrAl Fetuin-A immunoreActivity, suggesting A contribution to brAin development. We therefore Aimed At specifying Fetuin-A immunoreActivity in brAins of newborn rAts (Age P0–P28) And humAn neonAtes (20–40 weeks of gestAtion). In humAns And rAts, Fetuin-A wAs found in cortex, white mAtter, subplAte, hippocAmpus, subventriculAr zone, And ependymAl cells which supports A globAl role for brAin function. In rAts, overAll Fetuin-A immunoreActivity decreAsed with Age. At P0 Fetuin-A immunoreActivity Affected most brAin structures. ThereAfter, it becAme increAsingly restricted to distinct cells of the hippocAmpus, cingulAr gyrus, periventriculAr stem cell lAyer, And ependymA. In ependymAl cells the stAining pAttern complied with Active trAnsependymAl trAnsport from cerebrospinAl fluid. Double immunofluorescence studies reveAled colocAlizAtion with NeuN (mAture neurons), betA III tubulin (immAture neurons), GFAP (Astrocytes), And CD68 (ActivAted microgliA). This points to A role of Fetuin-A in different brAin functionAl systems. In humAn neonAtAl Autopsy cAses, frequently Affected from severe neurologicAl And non-neurologicAl diseAses, Fetuin-A immunoreActivity wAs heterogeneous And much less AssociAted with Age thAn in heAlthy tissues studied eArlier, suggesting An impAct of exogeneous noxious fActors on Fetuin-A regulAtion. Further reseArch on the role of Fetuin-A in the neonAtAl brAin during physiologicAl And pAthologicAl conditions is recommended. © 2012 Wiley PeriodicAls, Inc. Develop Neurobiol 73: 354–369, 2013

  • Fetuin-A Function in Systemic MinerAl MetAbolism
    Trends in Cardiovascular Medicine, 2012
    Co-Authors: Marietta Herrmann, Anne Kinkeldey, Willi Jahnen-dechent
    Abstract:

    Fetuin-A is A liver-derived plAsmA protein involved in cAlcified mAtrix metAbolism. Fetuin-A mediAtes the formAtion And stAbilizAtion of cAlciprotein pArticles (CPPs), soluble colloids mAde of Fetuin-A, further serum proteins, And cAlcium phosphAte minerAl. CPP formAtion ensures minerAl solubilizAtion And rApid cleArAnce from circulAtion by mAcrophAges of the mononucleAr phAgocyte system, thus preventing pAthologicAl cAlcificAtion. Accordingly, low levels of free serum Fetuin-A And high serum CPPs Are AssociAted with pAthologicAl cAlcificAtion in pAtients suffering from chronic kidney diseAse.

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  • Direct inhibitory effects of pioglitAzone on hepAtic Fetuin-A expression.
    PloS one, 2014
    Co-Authors: Akinobu Ochi, Katsuhito Mori, Masanori Emoto, Shinya Nakatani, Tomoaki Morioka, Koka Motoyama, Shinya Fukumoto, Yasuo Imanishi, Hidenori Koyama, Eiji Ishimura
    Abstract:

    Fetuin-A, A circulAting glycoprotein synthesized in the liver, is involved in insulin resistAnce And type 2 diAbetes. However, regulAtion of Fetuin-A synthesis hAs remAined obscure. We previously reported thAt pioglitAzone treAtment significAntly reduced serum Fetuin-A levels in pAtients with type 2 diAbetes. To clArify whether pioglitAzone cAn directory inhibit hepAtic Fetuin-A synthesis, we investigAted the effects of pioglitAzone on Fetuin-A expression both in vitro And in vivo. PioglitAzone treAtment suppressed mRNA And protein expression of Fetuin-A in FAo hepAtomA cells. Interestingly, rosiglitAzone but not metformin, Also inhibited Fetuin-A expression. In Addition, GW 9662, An inhibitor of peroxisome proliferAtor-ActivAted receptor (PPAR) γ, reversed pioglitAzone-induced suppression of Fetuin-A, suggesting thAt thiAzolidinedione derivAtives mAy hAve common chArActeristics with regArd to Fetuin-A suppression, possibly through PPARγActivAtion. FinAlly, orAl AdministrAtion of pioglitAzone to mice for 8 weeks resulted in suppression of hepAtic Fetuin-A mRNA. These findings suggest thAt pioglitAzone mAy pArtiAlly AmeliorAte insulin resistAnce through its direct inhibitory effects on Fetuin-A expression in the liver.

  • Fetuin-A And the cArdiovAsculAr system
    Advances in clinical chemistry, 2012
    Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki Inaba
    Abstract:

    Fetuin wAs first isolAted from bovine serum in 1944. It is now most commonly known As either Fetuin-A or AlphA-2-HS-glycoprotein (AHSG), the protein product of Ahsg gene. A prominent feAture of this protein is the functionAl diversity exerted in humAn physiology And pAthophysiology. Fetuin-A plAys A role in bone metAbolism, metAbolic disorders such As insulin resistAnce And diAbetes mellitus (DM), And centrAl nervous system (CNS) disorders such As ischemic stroke (IS) And neurodegenerAtive diseAses. In Addition, emerging evidence suggests involvement of Fetuin-A in the cArdiovAsculAr system. However, there Are mAny discordAnt findings on the AssociAtions between Fetuin-A And vAsculAr diseAses. In other words, it is unknown whether Fetuin-A is An exAcerbAting or A protective fActor in the cArdiovAsculAr system. One reAson for the seemingly inconsistent behAvior is the duAl functionAlity of Fetuin-A in vAsculAr diseAses where it cAn Act As An Atherogenic fActor or As A vAsculAr cAlcificAtion inhibitor. In Addition, the existence of confounding fActors such As DM And renAl dysfunction cAn veil the primAry AssociAtion between Fetuin-A And clinicAl pArAmeters. Considering these issues, we discuss the role of Fetuin-A for Atherosclerosis And vAsculAr cAlcificAtion in this review.

  • Fetuin-A: A multifunctionAl protein.
    Recent patents on endocrine metabolic & immune drug discovery, 2011
    Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki Inaba
    Abstract:

    Sixty-six yeArs hAve elApsed since the discovery of Fetuin in 1944, but its importAnce in mAmmAliAn physiology hAs only recently been AppreciAted. Fetuin, first isolAted from fetAl bovine serum And now most commonly known As either Fetuin-A, AlphA-2-HS-glycoprotein (recommended nAme by UniprotKB And PIR), or α2-HeremAns-Schmid glycoprotein, functions As An importAnt component of diverse normAl And pAthologicAl processes, including vAsculAr cAlcificAtion And bone metAbolism regulAtion, insulin resistAnce, proteAse Activity control, kerAtinocytes migrAtion, And breAst tumor cell proliferAtive signAling. Fetuin-A hAs Also been identified As A biomArker for neurodegenerAtive diseAse. Here, we summArize recent publicAtions focusing on the structurAl And functionAl properties of Fetuin-A. The emerging importAnce of Fetuin-A for both diAgnosis And therApeutics hAs come to the Attention of the phArmAceuticAl industry. Therefore, we will discuss the stAtus of pAtents bAsed on Fetuin-A.

  • Fetuin-A is AssociAted with cAlcified coronAry Artery diseAse.
    Coronary artery disease, 2010
    Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki Inaba, Hidenori Koyama, Eiji Ishimura, Tetsuo Shoji, Yuji Ikari, Shuichi Jono, Atsushi Shioi, Kazuhiro Hara
    Abstract:

    ObjectiveFetuin-A is A circulAting glycoprotein thAt is involved in vArious stAges of Atherosclerosis. Despite the fAct thAt emerging evidence suggests Fetuin-A Acts As A cAlcificAtion inhibitor thAt protects AgAinst AdvAnced cAlcified Atherosclerosis in diAlyzed pAtients, the role of Fetuin-A in cA

  • effects of pioglitAzone on serum Fetuin A levels in pAtients with type 2 diAbetes mellitus
    Metabolism-clinical and Experimental, 2008
    Co-Authors: Katsuhito Mori, Masanori Emoto, Masaaki Inaba, Hidenori Koyama, Takahiro Araki, Hisayo Yokoyama, Megumi Teramura, Eiko Lee, Tetsuo Shoji, Yoshiki Nishizawa
    Abstract:

    AbstrAct Fetuin-A (α2-HeremAns-Schmid glycoprotein), A circulAting glycoprotein, cAn inhibit insulin signAling both in vivo And in vitro. Recently, we And Another independent group hAve shown thAt Fetuin-A is positively AssociAted with insulin resistAnce in humAns. Furthermore, it hAs been reported thAt higher Fetuin-A levels Are AssociAted with metAbolic syndrome And Atherogenic lipid profiles. These dAtA suggest thAt Fetuin-A might be A regulAtor of insulin resistAnce And/or metAbolic syndrome. However, it is not cleAr how Fetuin-A levels Are regulAted. To Address this, we investigAted the effects of representAtive insulin-sensitizing therApies such As pioglitAzone, metformin, And Aerobic exercise on Fetuin-A levels. Twenty-seven pAtients with type 2 diAbetes mellitus were divided into pioglitAzone-treAted (Pio), metformin-treAted (Met), And exercise-treAted (Ex) groups. Ten pAtients in the Pio group And 9 pAtients in the Met group took 15 or 30 mg/d pioglitAzone or 500 or 750 mg/d metformin, respectively, for 6 months. Eight pAtients in the Ex group underwent A 3-month Aerobic exercise progrAm. Serum Fetuin-A levels were meAsured before And After eAch intervention. Intervention significAntly decreAsed hemoglobin A1c in All groups. After treAtment, serum Fetuin-A levels significAntly decreAsed in the Pio group (291.2 ± 57.7 to 253.1 ± 43.9 μg/mL, P = .006), whereAs there were no chAnges in serum Fetuin-A After intervention in either the Met or the Ex groups. We hypothesize thAt pioglitAzone could pArtiAlly AmeliorAte insulin resistAnce viA modulAting Fetuin-A levels.