ANGPTL8 function and development of coronary artery disease

• Project/Area Number: 26461359
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kanazawa University
• Principal Investigator: Nohara Atsushi 金沢大学, 医学系, 助教 (50313648)
• Co-Investigator(Renkei-kenkyūsha): INAZU Akihiro 金沢大学, 保健学系, 教授 (80293348) ; YAGI Kunimasa 金沢大学, 医学系, 准教授 (30293343) ; OKAZAKI Satoko 金沢大学, 医薬保健学総合研究科, 特任助教 (80613744)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ANGPTL8 / LPL / 冠動脈硬化症 / 脂質異常症 / 糖代謝異常 / 動脈硬化症 / 糖尿病 / リポ蛋白リパーゼ / Lipoprotein lipase / Diabetes mellitus / Coronary artery disease / HDL-cholesterol

Outline of Final Research Achievements

Betatrophin (ANGPTL8), also known as “Lipasin” (lipoprotein lipase inhibitor), has been reported as a dual-regulator of glucose and lipid metabolism, even if it may not proliferate pancreatic beta cell in human. Functional variant R59W in betatrophin gene is common in Japanese, but little is known about long-term impact of this gene variant, and also about the effect of lipid-lowering drugs on this hormone.
Betatrophin R59W variant may be beneficial for healthy group, but was worsening genetic contributor of metabolic disorder in presence of metabolic burden especially low LPL activity. On the impact of R59W variant in 10 years follow up on glucose metabolism, betatrophin R59W variant was a susceptibility factor of future diabetes mellitus with low LPL activity. Strong statin treatments slightly decreased betatrophin levels, but effect sizes were minimal.

Research Products

• [Journal Article] Lipid Management in a Japanese Community:Attainment Rate of Target Set by the Japan Atherosclerosis Society Guidelines for the Prevention of Atherosclerotic Cardiovascular Diseases 2012 (2017)
  • Author(s): Tada H, Kawashiri MA, Nohara A, Inazu A, Kobayashi J, Yasuda K, Mabuchi H, Yamagishi M, Hayashi K.
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 24 Issue: 3 Pages: 338-345
  • DOI: 10.5551/jat.36004
  • NAID: 130005397947
  • ISSN: 1340-3478, 1880-3873
  • Peer Reviewed / Open Access
• [Journal Article] Changes in lipoprotein lipase and endothelial lipase mass in familial hypercholesterolemia during three-drug lipid-lowering combination therapy (2016)
  • Author(s): Tada H, Kobayashi J, Kawashiri MA, Miyashita K, Nohara A, Inazu A, Nakajima K, Mabuchi H, Yamagishi M
  • Journal Title: Lipids Health Dis Volume: 15 Issue: 1 Pages: 66-66
  • DOI: 10.1186/s12944-016-0238-z
  • NAID: 120006325352
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and Safety of Alirocumab in Japanese Patients With Heterozygous Familial Hypercholesterolemia or at High Cardiovascular Risk With Hypercholesterolemia Not Adequately Controlled With Statins – ODYSSEY JAPAN Randomized Controlled Trial – (2016)
  • Author(s): Teramoto T, Kobayashi M, Tasaki H, Yagyu H, Higashikata T, Takagi Y, Uno K, Baccara-Dinet MT, Nohara A.
  • Journal Title: Circulation Journal Volume: 80 Issue: 9 Pages: 1980-1987
  • DOI: 10.1253/circj.CJ-16-0387
  • NAID: 130005406873
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Journal Article] Minimal contribution of severe hypertriglyceridemia in L-asparaginase-associated pancreatitis developed in a child with acute lymphocytic leukemia (2016)
  • Author(s): Goto Y, Nishimura R, Nohara A, Mase S, Fujiki T, Irabu H, Kuroda R, Araki R, Ikawa Y, Maeba H, Yachie A.
  • Journal Title: Rinsho Ketsueki Volume: 57 Issue: 8 Pages: 994-998
  • DOI: 10.11406/rinketsu.57.994
  • NAID: 130006882249
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Epicardial Adipose Tissue as a Predictor of Plaque Vulnerability in Patients With Mild Chronic Kidney Disease (2016)
  • Author(s): Nohara A.
  • Journal Title: Circulation Journal Volume: 80 Issue: 1 Pages: 64-66
  • DOI: 10.1253/circj.CJ-15-1265
  • NAID: 130005117012
  • ISSN: 1346-9843, 1347-4820
• [Journal Article] Exome sequencing in suspected monogenic dyslipidemias. (2015)
  • Author(s): Stitziel NO, Peloso GM, Abifadel M, Cefalu AB, Fouchier S, Motazacker MM, Tada H, Larach DB, Awan Z, Haller JF, Pullinger CR, Varret M, Noto D, Tarugi P, Kawashiri MA, Nohara A, Yamagishi M, Kathiresan S. et al.
  • Journal Title: Circ Cardiovasc Genet. Volume: 8 Issue: 2 Pages: 343-50
  • DOI: 10.1161/circgenetics.114.000776
  • Peer Reviewed / Open Access
• [Journal Article] Therapy: PCSK9 inhibitors for treating familial hypercholesterolaemia (2015)
  • Author(s): Mabuchi H, Nohara A.
  • Journal Title: Nat Rev Endocrinol Volume: 11 Issue: 1 Pages: 8-9
  • DOI: 10.1038/nrendo.2014.205
• [Journal Article] Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody. (2015)
  • Author(s): Hopkins PN, Defesche J, Fouchier SW, Yagi K, Krempf M, Swergold GD et. al.
  • Journal Title: Circ Cardiovasc Genet Volume: 8 Issue: 6 Pages: 823-831
  • DOI: 10.1161/circgenetics.115.001129
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Extreme Contrast of Postprandial Remnant-Like Particles Formed in Abetalipoproteinemia and Homozygous Familial Hypobetalipoproteinemia. (2015)
  • Author(s): Kawashiri MA, Tada H, Hashimoto M, Taniyama M, Nakano T, Nakajima K, Inoue T, Mori M, Nakanishi C, Konno T, Hayashi K, Nohara A, Inazu A, Koizumi J, Ishihara H, Kobayashi J, Hirano T, Mabuchi H, Yamagishi M.
  • Journal Title: JIMD Rep. Volume: in press Pages: 85-94
  • DOI: 10.1007/8904_2015_415
  • ISBN: 9783662474525, 9783662474532
  • Peer Reviewed / Open Access
• [Journal Article] Nohara A, Kobayashi J , Kawashiri MA, Tada H, Inazu A, Jiang M, Mabuchi H, Bujo H. Clinical significance of measuring soluble LR11, a circulating marker of atherosclerosis and HbA1c in familial hypercholesterolemia (2014)
  • Author(s): Nohara A, Kobayashi J , Kawashiri MA, Tada H, Inazu A, Jiang M, Mabuchi H, Bujo H
  • Journal Title: Clinical Biochemistry Volume: 47 Issue: 13-14 Pages: 1326-1328
  • DOI: 10.1016/j.clinbiochem.2014.05.003
  • Peer Reviewed / Open Access
• [Journal Article] Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation (2014)
  • Author(s): Mabuchi H, Nohara A, Noguchi T, Kobayashi J, Kawashiri MA, Inoue T, Mori M, Tada H, Nakanishi C, Yagi K, Yamagishi M, Ueda K, Takegoshi T, Miyamoto S, Inazu A, Koizumi J; The Hokuriku FH Study Group
  • Journal Title: Atherosclerosis Volume: 236 Issue: 1 Pages: 54-61
  • DOI: 10.1016/j.atherosclerosis.2014.06.005
  • Peer Reviewed / Open Access
• [Presentation] Clinical Characteristics of Double Heterozygotes With PCSK9 Gain-of-Function Mutations and LDLR Mutations (2016)
  • Author(s): Nohara A, Kawashiri M-A, Tada H, Yoshida M, Mori M, Nakanishi C, Yagi K, Inazu A, Yamaghishi M, Mabuchi H.
  • Organizer: American Heart Association Scientific Sessions 2016
  • Place of Presentation: New Orleans
  • Year and Date: 2016-12-12
  • Int'l Joint Research
• [Presentation] Clinical Characteristics of Common PCSK9 Gain-of-Function E32K Variant with Higher TG Elevation, and Double Heterozygotes with Common PCSK9 Variants and LDLR mutations (2016)
  • Author(s): Nohara A, Kawashiri M-A, Tada H, Yoshida M, Mori M, Nakanishi C, Yagi K, Inazu A, Yamaghishi M, Mabuchi H.
  • Organizer: 84th European Atherosclerosis Society Congress 2016
  • Place of Presentation: Innsbruck
  • Year and Date: 2016-05-29
  • Int'l Joint Research
• [Presentation] Impact of Betatrophin (ANGPTL8) R59W Mutation For Future Diabetes (2015)
  • Author(s): Nohara A, Kawashiri M,Hattori H, Iwasaki T, Liu J, Yagi K, Yoshida M, Tada H, Mori M, Nakanishi C, Inazu A, Kobayashi A, Yamagishi M, Mabuchi M.
  • Organizer: American Heart Association Scientific Sessions 2015
  • Place of Presentation: 米国 オーランド
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] Metabolic Burden Switches Impact of Betatrophin (ANGPTL8) R59W Mutation From Atheroprotective to Atherogenic Lipid Profiles (2014)
  • Author(s): Nohara A, Yagi K, Liu J, Ohbatake A, Okazaki S, Yoshida M, Mori M, Nakanishi C, Tada H, Kawashiri M-A, Inazu A, Yamaghishi M, Mabuchi H.
  • Organizer: American Heart Association Scientific Sessions 2014
  • Place of Presentation: Chicago, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Genetic CETP Deficiency Associated With Higher eGFR and Lower Coronary Stenosis Index in Dyslipdemic Patients in Japan (2014)
  • Author(s): Nohara A, Inazu A, Okazaki S, Yoshida M, Mori M, Nakanishi C, Tada H, Kawashiri M-A, Yagi K, Yamaghishi M, Mabuchi H.
  • Organizer: American Heart Association Scientific Sessions 2014
  • Place of Presentation: Chicago, USA
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] Impact of Loss of Function Variant of Betatrophin on Advanced Coronary Artery Disease Among Diabetic Patients in Japan (2014)
  • Author(s): Nohara A, Yagi K, Liu J, Ohbatake A, Okazaki S, Yoshida M, Mori M, Nakanishi C, Tada H, Kawashiri M-A, Inazu A, Yamaghishi M, Mabuchi H.
  • Organizer: 82nd European Atherosclerosis Society Congress
  • Place of Presentation: Madrid, Spain
  • Year and Date: 2014-05-31 – 2014-06-03