Systematic Analysis of Pathophysiology of Familial Hypercholesterolemia Due to Different Causal Gene Mutations

• Project/Area Number: 21591160
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kanazawa University
• Principal Investigator: KAWASHIRI Masaaki 金沢大学, 附属病院, 講師 (90345637)
• Co-Investigator(Kenkyū-buntansha): NOGUCHI Tohru 金沢大学, 医学系・研究科, 助教 (40456421)
• Co-Investigator(Renkei-kenkyūsha): IKEWAKI Katsunori 防衛医科大学校, 老年内科, 教授 (40287199)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 脂質代謝異常 / 家族性高コレステロール血症 / 安定同位体 / 常染色体劣性高コレステロール血症 / PCSK9

Research Abstract

The fractional catabolic rate(FCR) of low-density lipoprotein(LDL) apolipoprotein B(apoB) in a patient with autosomal recessive hypercholesterolemia(ARH) was 75% smaller, whereas direct removal of very-LDL apoB was dramatically greater compared with those of normal control subjects. Statin therapy normalized FCR of LDL apoB and increased direct removal of very-LDL in ARH patient. On the other hand, the FCR of patients with homozygous proprotein convertase subtilisin/kexin 9(PCSK9) gene mutation was 52% smaller than that of normal control subjects and normalized by statin therapy. Whereas, both production rate and direct removal of very-LDL was increased compared with those of normal control subjects, which were not changed by statin therapy.

Research Products

• [Journal Article] Altered metabolism of low-density lipoprotein and very-low-density lipoprotein remnant in autosomal recessive hypercholesterolemia : results from stable isotope kinetic study in vivo (2012)
  • Author(s): Tada H, Kawashiri MA, Ikewaki K, Terao Y, Noguchi T, Nakanishi C, Tsuchida M, Takata M, Miwa K, Konno T, Hayashi K, Nohara A, Inazu A, Kobayashi J, Mabuchi H, Yamagishi M
  • Journal Title: Circ Cardiovasc Genet Volume: 5 Issue: 1 Pages: 35-41
  • DOI: 10.1161/circgenetics.111.960948
  • Peer Reviewed
• [Journal Article] Novel mutations of cholesteryl ester transfer protein(CETP) gene in Japanese hyperalphalipoproteinemic subjects (2012)
  • Author(s): Ohtani R, Inazu A, Noji Y, Wakasugi T, Miwa K, Tada H, Kawashiri MA, Noguchi T, Nohara A, Kobayashi J, Koizumi J, Yamagishi M, Mabuchi H
  • Journal Title: Clin Chim Acta Volume: 413 Issue: 5-6 Pages: 537-43
  • DOI: 10.1016/j.cca.2011.11.010
  • NAID: 120004026116
  • Peer Reviewed
• [Journal Article] Efficacy and safety of coadministration of rosuvastatin, ezetimibe, and colestimide in heterozygous familial hypercholesterolemia (2012)
  • Author(s): Kawashiri MA, Nohara A, Noguchi T, Tada H, Nakanishi C, Mori M, Konno T, Hayashi K, Fujino N, Inazu A, Kobayashi J, Mabuchi H, Yamagishi M
  • Journal Title: Am J Cardiol Volume: 109 Issue: 3 Pages: 364-9
  • DOI: 10.1016/j.amjcard.2011.09.019
  • Peer Reviewed
• [Journal Article] Impact of out-stent plaque volume on in-stent intimal hyperplasia : Results from serial volumetric analysis with high-gain intravascular ultrasound (2012)
  • Author(s): Tada H, et al., 計10名、2番目
  • Journal Title: Int J Cardiol Volume: (掲載確定) Issue: 2 Pages: 235-239
  • DOI: 10.1016/j.ijcard.2011.01.058
  • Peer Reviewed
• [Journal Article] Insulin secretion and insulin sensitivity on the oral glucose tolerance test (OGTT)in middle-aged Japanese (2012)
  • Author(s): Oka R, et al., 計10名、7番目
  • Journal Title: Endocr J Volume: 59 Pages: 55-64
  • Peer Reviewed
• [Journal Article] A novel type of familial hypercholesterolemia : double heterozygous mutations in LDL receptor and LDL receptor adaptor protein 1 gene (2011)
  • Author(s): Tada H, Kawashiri MA, Ohtani R, Noguchi T, Nakanishi C, Konno T, Hayashi K, Nohara A, Inazu A, Kobayashi J, Mabuchi H, Yamagishi M
  • Journal Title: Atherosclerosis Volume: 219 Issue: 2 Pages: 663-6
  • DOI: 10.1016/j.atherosclerosis.2011.08.004
  • NAID: 120003368152
  • Peer Reviewed
• [Journal Article] Impact of bezafibrate and atorvastatin on lipoprotein subclass in patients with type III hyperlipoproteinemia : result from a crossover study (2011)
  • Author(s): Kawashiri MA, Kobayashi J, Nohara A, Noguchi T, Tada H, Nakanishi C, Inazu A, Mabuchi H, Yamagishi M
  • Journal Title: Clin Chim Acta Volume: 412 Issue: 11-12 Pages: 1068-75
  • DOI: 10.1016/j.cca.2011.02.026
  • Peer Reviewed
• [Journal Article] Hokuriku FH Study Group. Molecular genetic epidemiology of homozygous familial hypercholesterolemia in the Hokuriku district of Japan (2011)
  • Author(s): Mabuchi H, Nohara A, Noguchi T, Kobayashi J, Kawashiri MA, Tada H, Nakanishi C, Mori M, Yamagishi M, Inazu A, Koizumi J
  • Journal Title: Atherosclerosis Volume: 214 Issue: 2 Pages: 404-407
  • DOI: 10.1016/j.atherosclerosis.2010.11.005
  • Peer Reviewed
• [Journal Article] Comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus : results from a crossover study (2011)
  • Author(s): Noguchi T, et al., 計14名、9番目
  • Journal Title: Atherosclerosis Volume: 217 Issue: 1 Pages: 165-170
  • DOI: 10.1016/j.atherosclerosis.2011.02.012
  • NAID: 120003141452
  • Peer Reviewed
• [Journal Article] Expression profiling of the ephrin (EFN)and Eph receptor (EPH) family of genes in atherosclerosis-related human cells (2011)
  • Author(s): Sakamoto A, et la., 計9名、7番目
  • Journal Title: J Int Med Res Volume: 39 Pages: 522-527
  • Peer Reviewed
• [Journal Article] Impact of severe coronary disease associated or not associated with diabetes mellitus on outcome of interventional treatment using stents : results from HERZ (Heart Research Group of Kanazawa) analyses (2011)
  • Author(s): Uchiyama K, et al., 計25名、24番目
  • Journal Title: J Int Med Res Volume: 39 Pages: 549-557
  • Peer Reviewed
• [Journal Article] Gene and Protein Expression Analysis of Mesenchymal Stem Cells Derived From Rat Adipose Tissue and Bone Marrow (2011)
  • Author(s): Nakanishi C, et al., 計10名、8番目
  • Journal Title: Circulation Journal Volume: 75 Issue: 9 Pages: 2260-2268
  • DOI: 10.1253/circj.CJ-11-0246
  • NAID: 10029340006
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Intravascular ultrasound appearance of scattered necrotic core as an index for deterioration of coronary flow during intervention in acute coronary syndrome (2011)
  • Author(s): Sakata K, et al., 計9名、2番目
  • Journal Title: Hear Vessels Volume: (掲載確定) Issue: 5 Pages: 443-452
  • DOI: 10.1007/s00380-011-0175-8
  • Peer Reviewed
• [Journal Article] Molecular genetic epidemiology of homozygous familial hyperchole sterolemia in the Hokuriku district of Japan. (2011)
  • Author(s): Mabuchi H, et al.(計11名、5番目)
  • Journal Title: Atherosclerosis Volume: 214 Pages: 404-407
  • Peer Reviewed
• [Journal Article] Identification of a Novel Missense Mutation in the Sterol 27-Hydroxylase Gene in Two Japanese Patients with Cerebrotendinous Xanthomatosis (2010)
  • Author(s): Nozue T, Higashikata T, Inazu A, Kawashiri MA, Nohara A, Kobayashi J, Koizumi J, Yamagishi M, Mabuchi H
  • Journal Title: Internal Medicine Volume: 49 Issue: 12 Pages: 1127-1131
  • DOI: 10.2169/internalmedicine.49.3277
  • NAID: 130000251640
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed
• [Journal Article] The E32K variant of PCSK9 exacerbates the phenotype of familial hypercholesterolaemia by increasing PCSK9 function and concentration in the circulation (2010)
  • Author(s): Noguchi T, Katsuda S, Kawashiri MA, Tada H, Nohara A, Inazu A, Yamagishi M, Kobayashi J, Mabuchi H
  • Journal Title: Atherosclerosis Volume: 210 Issue: 1 Pages: 166-72
  • DOI: 10.1016/j.atherosclerosis.2009.11.018
  • Peer Reviewed
• [Journal Article] The E32K variant of PCSK9 exacerbates the phenotype of familial hype rcholesterolaemia by increasing PCSK9 function and concentration in the circulation. (2010)
  • Author(s): Noguchi T, et al.(計9名、3番目)
  • Journal Title: Atherosclerosis. Volume: 210 Pages: 166-172
  • Peer Reviewed
• [Journal Article] Impacts of visceral adipose tissue and subcutaneous adipose tissue on metabolic risk factors in middle-aged Japanese. (2010)
  • Author(s): Oka R, et al.(計17名、14番目)
  • Journal Title: Obesity Volume: 18 Pages: 153-160
  • Peer Reviewed
• [Journal Article] Cholesterol efflux from J774 macrophages and Fu5AH hepatoma cells to serum is preserved in CETP-deficient patients (2009)
  • Author(s): Miwa K, Inazu A, Kawashiri MA, Nohara A, Higashikata T, Kobayashi J, Koizumi J, Nakajima K, Nakano T, Niimi M, Mabuchi H, Yamagishi M
  • Journal Title: Clin ChimActa Volume: 402 Issue: 1-2 Pages: 19-24
  • DOI: 10.1016/j.cca.2008.12.012
  • Peer Reviewed
• [Journal Article] Formation of prebeta1-HDL during lipolysis of triglyceride-rich lipoprotein (2009)
  • Author(s): Miyazaki O, Fukamachi I, Mori A, Hashimoto H, Kawashiri MA, Nohara A, Noguchi T, Inazu A, Yamagishi M, Mabuchi H, Kobayashi J
  • Journal Title: BiochemBiophys Res Commun Volume: 379 Issue: 1 Pages: 55-9
  • DOI: 10.1016/j.bbrc.2008.11.146
  • Peer Reviewed
• [Journal Article] Cholesterol efflux from J774 macrophages and Fu5AH hepatoma cells to serum is preserved in CETP-deficient patients (2009)
  • Author(s): Miwa K, Kawashiri M (計12名、3番目)
  • Journal Title: Clin Chim Acta. 402 Pages: 19-24
  • Peer Reviewed
• [Journal Article] Apolipoprotein B gene mutations and fatty liver in Japanese hypobetali poproteinemia (2009)
  • Author(s): Katsuda S, Kawashiri M (計13名、2番目)
  • Journal Title: Clin Chim Acta. 399 Pages: 64-68
  • Peer Reviewed
• [Journal Article] A novel method for determining functional LDL receptor activity in familial hypercholesterolemia : application of the CD3/CD28 assay in lymphocytes (2009)
  • Author(s): Tada H, Kawashiri M (計12名、2番目)
  • Journal Title: Clin Chim Acta. 400 Pages: 42-47
  • NAID: 120001063575
  • Peer Reviewed
• [Journal Article] (2009)
  • Author(s): 川尻剛照, 多田隼人, 山岸正和
  • Journal Title: 炎症・再生医学事典 (共著) 虚血性心疾患・動脈硬化(朝倉書店) Pages: 251-255
• [Presentation] et al. Impact of impaired LDL catabolism and increased VLDL and VLDL remnant production on hypercholesterolemia in homozygous PCSK9 mutation : Evidence from a kinetic study with stable isotope (2011)
  • Author(s): Masaaki Kawashiri, Katsunori Ikewaki, Tohru Noguchi
  • Organizer: 84^<th> American Heart Association 2011 Scientific Sessions
  • Place of Presentation: Orange County Convention Center, Orlando, USA
• [Presentation] パネルディスカッション多剤併用による積極的脂質管理と新規脂質低下剤の可能性 (2011)
  • Author(s): 川尻剛照
  • Organizer: 第59回日本心臓病学会学術集会
  • Place of Presentation: 神戸国際会議場(神戸、兵庫県)
• [Presentation] Impact of elevated PCSK9 levels on regulation of LDL-cholesterol after statin treatment : Study with different types of lipid lowering drugs (2011)
  • Author(s): 川尻剛照,野口徹, ほか
  • Organizer: 第75回日本循環器学会総会・学術集会
  • Place of Presentation: パシフィコ横浜(横浜、神奈川県)
• [Presentation] Impaired LDL catabolism and increased VLDL and VLDL remnant production in homozygous familial hypercholesterolemia with PCSK9 gene mutation (2011)
  • Author(s): 川尻剛照,池脇克則,野口徹, ほか
  • Organizer: 第75回日本循環器学会総会・学術集会
  • Place of Presentation: パシフィコ横浜(横浜、神奈川県)
• [Presentation] Impact of elevated PCSK9 levels on regulation of LDL-cholesterol after statin treatment : Study with different typesof lipid lowering drugs (2011)
  • Author(s): Masaaki Kawashiri, Katsunori Ikewaki, Tohru Noguchi, et al
  • Organizer: 60^<th> Annual Scientific Session of American College of Cardiology
  • Place of Presentation: Ernest N. Morial Convention Center, New Orleans,(USA)
• [Presentation] Impact of elevated PCSK9 legels on regulation of LDL-cholesterol after statin treatment : Study with different types of lipid lowering drugs (2011)
  • Author(s): Kawashiri M, et al., 計8名、1番目
  • Organizer: 60^<th> Annual Scientific Session of American College of Cardiology
  • Place of Presentation: Ernest N. Morial Conventi on Center (アメリカ)
• [Presentation] Impact of impared LDL catabolism and increased VLDL and VLDL remnant production on hypercholesterolemia in homozygous PCSK9 gene mutation : Evidence from kinetic study with stable isotope (2011)
  • Author(s): Kawashiri M, et al., 計9名、1番目
  • Organizer: American Heart Association Scientific Sessions 2011
  • Place of Presentation: Orange County Convention Center(アメリカ)
• [Presentation] パネルディスカッション多剤併用による積極的脂質管理と新規脂質低下剤の可能性 (2011)
  • Author(s): 川尻剛照、野原淳、馬渕宏、山岸正和
  • Organizer: 第59回日本心臓病学会学術集会
  • Place of Presentation: 神戸国際会議場(兵庫県)
• [Presentation] 脂質異常症とLDLアフェレシス「FHヘテロ接合体とLDLアフェレシス」 (2010)
  • Author(s): 川尻剛照
  • Organizer: 第31回日本アフェレシス学会学術大会
  • Place of Presentation: ディズニーアンバサダーホテル(千葉県)(招待講演)
  • Year and Date: 2010-11-05
• [Presentation] Impact of the LDL-receptor-related molecules on the achievement of optimal LDL cholesterol level : Evidence from newly identified gene mutations (2010)
  • Author(s): 川尻剛照, 多田隼人, 中西千明, 山岸正和, 野口徹, 野原淳, 小林淳二, 馬渕宏, 池脇克則
  • Organizer: 第74回日本循環器学会総会・学術集会シンポジウム
  • Place of Presentation: グランドプリンスホテル京都 (京都府)
  • Year and Date: 2010-03-05
• [Presentation] Elevation of PCSK9 levels after statin therapy : study with different types of lipid lowering drugs (2010)
  • Author(s): 川尻剛照,野口徹, ほか
  • Organizer: 第43回日本動脈硬化学会総会・学術集会
  • Place of Presentation: ロイトン札幌(札幌、北海道)
• [Presentation] ワークショップFHヘテロ接合体とLDLアフェレーシス (2010)
  • Author(s): 川尻剛照
  • Organizer: 第31回日本アフェレシス学会学術大会
  • Place of Presentation: ディズニーアンバサダーホテル(幕張、千葉県)
• [Presentation] The effects of combination therapy with permitted maximum doses of rosuvastatin, ezetimibe and colestimide in patients with heterozygous familial hypercholesterolemia (2010)
  • Author(s): 川尻剛照
  • Organizer: 第75回日本循環器学会総会・学術集会
  • Place of Presentation: 長良川国際会議場(岐阜、岐阜県)
• [Presentation] シンポジウムImpact of the LDL-receptor-related molecules on achievement of optimal LDL cholesterol level : evidence from newly identified gene mutations (2010)
  • Author(s): 川尻剛照
  • Organizer: 第74回日本循環器学会総会・学術集会
  • Place of Presentation: 国立京都国際会館(京都、京都府)
• [Presentation] Enhanced effect of bezafibrate on HDL subfraction in patients with dysbetalipoproteinemia : Results from a crossover study with atorvastatin (2009)
  • Author(s): Masaaki Kawashiri
  • Organizer: 2009 International Symposium on Atherosclerosis
  • Place of Presentation: Hynes Convention Center, Boston, USA
• [Presentation] Impact of co-administration of atorvastatin annd bezafibrate on the lipoprotein subclass : Comparison between apoE2/2 and E3/3 (2009)
  • Author(s): Masaaki Kawashiri
  • Organizer: 17^<th> Asian Pacific Congress of Cardiology
  • Place of Presentation: International Conference Center(Kyoto)
• [Book] 成功に導くPCI治療戦略低HDL-Cは改善すべきか (2012)
  • Author(s): 川尻剛照
  • Publisher: 南江堂
• [Book] 分子予防環境医学(共著) 動脈硬化症 (2010)
  • Author(s): 川尻剛照、山岸正和
  • Total Pages: 13
  • Publisher: 本の泉社