Pathophysiology and therapeutic strategy of autoimmune hypertriglyceridemia.

• Project/Area Number: 20KK0190
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research (B))
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 52:General internal medicine and related fields
• Research Institution: Gunma University
• Principal Investigator: Murakami Masami 群馬大学, 大学院医学系研究科, 教授 (30241871)
• Co-Investigator(Kenkyū-buntansha): 中嶋 克行 高崎健康福祉大学, 健康福祉学部, 客員教授 (10444051) ; 常川 勝彦 群馬大学, 医学部附属病院, 講師 (30436307) ; 青木 智之 群馬大学, 医学部附属病院, 助教 (60710580) ; 長澤 拓海 群馬大学, 医学部附属病院, 技術職員 (70890648) ; 木村 孝穂 群馬大学, 大学院医学系研究科, 准教授 (90396656)
• Project Period (FY): 2020-10-27 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2022: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2021: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2020: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 脂質異常症 / 自己抗体 / トリグリセライド / リポ蛋白リパーゼ / 遺伝子変異

Outline of Research at the Start

トリグリセライド（TG）を多く含むリポ蛋白（TG-richリポ蛋白）は、リポ蛋白リパーゼ（LPL）によって代謝される。LPLは筋細胞や脂肪細胞で産生され、毛細血管内皮細胞に存在するGPIHBP1と呼ばれるアンカー蛋白によって血管内腔に輸送されてTG-richリポ蛋白を代謝する。研究代表者らは、GPIHBP1に対する自己抗体によってLPLが血管内腔に輸送されなくなり、著しい高TG血症をきたす症例を報告した。研究代表者および研究分担者が海外の共同研究機関を訪問して研究を推進し、GPIHBP1自己抗体による自己免疫性高TG血症の病態を解明し、その治療戦略を創出する。

Outline of Final Research Achievements

Lipoprotein lipase (LPL) hydrolyzes triglycerides in lipoproteins. LPL is secreted by adipocytes and myocytes, and transported across endothelial cells to the capillary lumen by GPIGBP1, the cell-surface protein of endothelial cells.
During the process of the development of GPIHBP1 ELISA, we encountered the plasma samples from patients with hypertriglyceridemia. These patients were demonstrated to have autoantibodies against GPIHBP1 which abolished the capacity of GPIHBP1 to bind LPL. The patients with GPIHBP1 autoantibody syndrome showed extremely high triglyceride concentrations with low LPL levels, and most of them experienced acute pancreatitis. GPIHBP1 autoantibody syndrome were frequently found in young female subjects. Most of the patients had other autoimmune diseases, and immunosuppressive treatment by Rituximab resulted in the normalization of triglyceride levels accompanied by the disappearance of GPIHBP1 autoantibodies in some patients.

Academic Significance and Societal Importance of the Research Achievements

リポ蛋白リパーゼ（LPL）は脂肪細胞や筋細胞で産生され、毛細血管内皮細胞膜上に存在するアンカー蛋白GPIHBP1に結合して血管内腔に輸送され、トリグリセライド（TG）を代謝する。我々は、GPIHBP1に対する自己抗体により血中LPL活性が低下し、著明な高TG血症を来した症例を見出し、GPIHBP1自己抗体症候群という新たな自己免疫性脂質異常の疾患概念を確立した。本症候群は、若年女性例が多く、他の自己免疫疾患を合併し、急性膵炎を繰り返すことが多いことが明らかとなった。治療にリツキシマブが有効である症例が存在することから、新たな脂質異常症の治療法の創出につながる可能性が示唆された。

Research Products

• [Int'l Joint Research] カリフォルニア大学ロサンゼルス校(米国)
• [Int'l Joint Research] コペンハーゲン大学(デンマーク)
• [Int'l Joint Research] 南京大学(中国)
• [Int'l Joint Research] カリフォルニア大学ロサンゼルス校(米国)
• [Int'l Joint Research] コペンハーゲン大学(デンマーク)
• [Int'l Joint Research] 南京(中国)
• [Int'l Joint Research] カリフォルニア大学ロサンゼルス校(米国)
• [Int'l Joint Research] コペンハーゲン大学(デンマーク)
• [Int'l Joint Research] 南京大学(中国)
• [Journal Article] A case of hyperchylomicronemia associated with GPIHBP1 autoantibodies and fluctuating thyroid autoimmune disease (2023)
  • Author(s): Nozue Tsuyoshi、Tada Hayato、Murakami Masami、Michishita Ichiro
  • Journal Title: Journal of Clinical Lipidology Volume: 17 Issue: 1 Pages: 68-72
  • DOI: 10.1016/j.jacl.2022.10.005
  • Peer Reviewed / Open Access
• [Journal Article] 自己抗体による高トリグリセライド血症 (2023)
  • Author(s): 村上正巳
  • Journal Title: 糖尿病・内分泌代謝科 Volume: 56 Pages: 205-212
• [Journal Article] GPIHBP1に対する自己抗体による高トリグリセライド血症 (2023)
  • Author(s): 村上正巳
  • Journal Title: Medical Practice Volume: 40 Pages: 95-97
• [Journal Article] GPIHBP1 autoantibody is an independent risk factor for the recurrence of hypertriglyceridemia-induced acute pancreatitis (2022)
  • Author(s): Zhang Guofu、Yang Qi、Mao Wenjian、Hu Yuepeng、Pu Na、Deng Hongbin、Yu Xianqiang、Zhang Jingzhu、Zhou Jing、Ye Bo、Li Gang、Li Baiqiang、Ke Lu、Tong Zhihui、Murakami Masami、Kimura Takao、Nakajima Katsuyuki、Cao Wangsen、Liu Yuxiu、Li Weiqin
  • Journal Title: Journal of Clinical Lipidology Volume: 16 Issue: 5 Pages: 626-634
  • DOI: 10.1016/j.jacl.2022.08.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of hypertriglyceridemia due to GPIHBP1 autoantibodies prior to clinical diagnosis of systemic lupus erythematosus in a 14-year-old girl (2022)
  • Author(s): Kunitsu Tomoaki、Harada-Shiba Mariko、Sato Tomomi、Nonomura Kazuo、Kimura Takao、Miyashita Kazuya、Nakajima Katsuyuki、Murakami Masami
  • Journal Title: Allergology International Volume: 71 Issue: 4 Pages: 555-557
  • DOI: 10.1016/j.alit.2022.05.001
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Differences in stress response between two altitudes assessed by salivary cortisol levels within circadian rhythms in long-distance runners (2022)
  • Author(s): Tsunekawa Katsuhiko、Ushiki Kazumi、Martha Larasati、Nakazawa Asuka、Hasegawa Rika、Shimizu Risa、Shimoda Nozomi、Yoshida Akihiro、Nakajima Kiyomi、Kimura Takao、Murakami Masami
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 9749-9749
  • DOI: 10.1038/s41598-022-13965-w
  • Peer Reviewed / Open Access
• [Journal Article] Age-Related Sex Differences in Glucose Tolerance by 75 g Oral Glucose Tolerance Test in Japanese (2022)
  • Author(s): Yoshida Akihiro、Kimura Takao、Tsunekawa Katsuhiko、Shoho Yoshifumi、Yanagawa Yoshimaro、Araki Osamu、Aoki Tomoyuki、Ogiwara Takayuki、Murakami Masami
  • Journal Title: Nutrients Volume: 14 Issue: 22 Pages: 4868-4868
  • DOI: 10.3390/nu14224868
  • Peer Reviewed / Open Access
• [Journal Article] Serological Screening of Immunoglobulin G against SARS-CoV-2 Nucleocapsid and Spike Protein before and after Two Vaccine Doses among Healthcare Workers in Japan (2022)
  • Author(s): Hiramoto Suguru、Miyashita Daichi、Kimura Takao、Niwa Takahiko、Uchida Azusa、Sano Maika、Murata Mai、Nagasawa Takumi、Tsunekawa Katsuhiko、Aoki Tomoyuki、Yoshida Akihiro、Kato Toshimitsu、Yanagisawa Kunio、Tokue Yutaka、Murakami Masami
  • Journal Title: The Tohoku Journal of Experimental Medicine Volume: 257 Issue: 1 Pages: 57-64
  • DOI: 10.1620/tjem.2022.J017
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access
• [Journal Article] 抗GPIHBP1抗体による高トリグリセライド血症 (2022)
  • Author(s): 村上正巳、常川勝彦、木村孝穂、中嶋克行
  • Journal Title: 糖尿病・内分泌代謝科 Volume: 55 Pages: 752-758
• [Journal Article] Examination of Conditions for External Quality Control in Identification of Microorganisms using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (2022)
  • Author(s): SOGAWA KAZUYUKI、UECHI KOHEI、KIYOSUKE MAKIKO、MURATA SYOTA、KUSABA KOJI、SAEKI YUJI、HORIUCHI KAZUKI、YASUDA KAZUNARI、OKUMURA HAJIME、FUJINAGA AZUMI、MURAKAMI MASAMI
  • Journal Title: Biocontrol Science Volume: 27 Issue: 3 Pages: 179-184
  • DOI: 10.4265/bio.27.179
  • ISSN: 1342-4815, 1884-0205
  • Peer Reviewed / Open Access
• [Journal Article] Electrostatic sheathing of lipoprotein lipase is essential for its movement across capillary endothelial cells (2022)
  • Author(s): Song Wenxin、Beigneux Anne P.、Winther Anne-Marie L.、Kristensen Kristian K.、Gr?nnemose Anne L.、Yang Ye、Tu Yiping、Munguia Priscilla、Morales Jazmin、Jung Hyesoo、de Jong Pieter J.、Jung Cris J.、Miyashita Kazuya、Kimura Takao、Nakajima Katsuyuki、Murakami Masami、et al.
  • Journal Title: Journal of Clinical Investigation Volume: 132 Issue: 5
  • DOI: 10.1172/jci157500
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association Between Insulin Resistance and Cardinal Rheological Parametersin Young Healthy Japanese Individuals During 75g Oral Glucose ToleranceTest (2022)
  • Author(s): Martha Larasati、Kimura Takao、Yoshida Akihiro、Tsunekawa Katsuhiko、Aoki Tomoyuki、Araki Osamu、Nara Makoto、Ogiwara Takayuki、Sumino Hiroyuki、Murakami Masami
  • Journal Title: Endocrine, Metabolic & Immune Disorders - Drug Targets Volume: 22 Issue: 1 Pages: 125-132
  • DOI: 10.2174/1871530321666210720124554
  • Peer Reviewed / Open Access
• [Journal Article] Endothelial Lipase Exerts its Anti-Atherogenic Effect through Increased Catabolism of β-VLDLs (2021)
  • Author(s): Yan H, Niimi M, Wang C, Chen Y, Zhou H, Matsuhida F, Nishijima K, Kitajima S, Nakajima K, Murakami M, Zhang J, Chen YE, Fan J
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 28 Issue: 2 Pages: 157-168
  • DOI: 10.5551/jat.55244
  • NAID: 130007979538
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2021-02-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association between high normal-range thyrotropin concentration and carotid intima-media thickness in euthyroid premenopausal, perimenopausal and postmenopausal women (2021)
  • Author(s): Sakamaki Koji、Tsunekawa Katsuhiko、Ishiyama Nobuyoshi、Kudo Mizuho、Ando Kimiko、Akuzawa Masako、Nakajima Katsuyuki、Shimomura Yohnosuke、Araki Osamu、Kimura Takao、Murakami Masami
  • Journal Title: Maturitas Volume: 144 Pages: 29-36
  • DOI: 10.1016/j.maturitas.2020.10.022
  • Peer Reviewed / Open Access
• [Journal Article] Konjac Glucomannan Attenuated Triglyceride Metabolism during Rice Gruel Tolerance Test (2021)
  • Author(s): Nagasawa Takumi、Kimura Takao、Yoshida Akihiro、Tsunekawa Katsuhiko、Araki Osamu、Ushiki Kazumi、Ishigaki Hirotaka、Shoho Yoshifumi、Suda Itsumi、Hiramoto Suguru、Murakami Masami
  • Journal Title: Nutrients Volume: 13 Issue: 7 Pages: 2191-2191
  • DOI: 10.3390/nu13072191
  • Peer Reviewed / Open Access
• [Journal Article] Significance of serum branched-chain amino acid to tyrosine ratio measurement in athletes with high skeletal muscle mass (2021)
  • Author(s): Tsunekawa Katsuhiko、Matsumoto Ryutaro、Ushiki Kazumi、Martha Larasati、Shoho Yoshifumi、Yanagawa Yoshimaro、Ishigaki Hirotaka、Yoshida Akihiro、Araki Osamu、Nakajima Kiyomi、Kimura Takao、Murakami Masami
  • Journal Title: BMC Sports Science, Medicine and Rehabilitation Volume: 13 Issue: 1 Pages: 1-1
  • DOI: 10.1186/s13102-020-00229-1
  • Peer Reviewed / Open Access
• [Journal Article] Chylomicronemia from GPIHBP1 autoantibodies (2020)
  • Author(s): Miyashita Kazuya、Lutz Jens、Hudgins Lisa C.、Toib Dana、Ashraf Ambika P.、Song Wenxin、Murakami Masami、Nakajima Katsuyuki、Ploug Michael、Fong Loren G.、Young Stephen G.、Beigneux Anne P.
  • Journal Title: Journal of Lipid Research Volume: 61 Issue: 11 Pages: 1365-1376
  • DOI: 10.1194/jlr.r120001116
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The antagonic behavior of GPIHBP1 between EAT and circulation does not reflect lipolytic enzymes levels in the tissue and serum from coronary patients (2020)
  • Author(s): Barchuk Magali、Nagasawa Takumi、Murakami Masami、Lopez Graciela、Baldi Julio、Miksztowicz Veronica、Rubio Miguel、Schreier Laura、Nakajima Katsuyuki、Berg Gabriela
  • Journal Title: Clinica Chimica Acta Volume: 510 Pages: 423-429
  • DOI: 10.1016/j.cca.2020.08.001
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Apolipoprotein CIII Deficiency Protects Against Atherosclerosis in Knockout Rabbits (2020)
  • Author(s): Yan Haizhao、Niimi Manabu、Matsuhisa Fumikazu、Zhou Huanjin、Kitajima Shuji、Chen Yajie、Wang Chuan、Yang Xiawen、Yao Jian、Yang Dongshan、Zhang Jifeng、Murakami Masami、Nakajima Katsuyuki、Wang Yao、Liu Enqi、Liang Jingyan、Chen Y. Eugene、Fan Jianglin
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 40 Issue: 9 Pages: 2095-2107
  • DOI: 10.1161/atvbaha.120.314368
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Chylomicronemia From GPIHBP1 Autoantibodies Successfully Treated With Rituximab: A Case Report (2020)
  • Author(s): Lutz Jens、Dunaj-Kazmierowska Malgorzata、Arcan Sven、Kassner Ursula、Miyashita Kazuya、Murakami Masami、Ploug Michael、Fong Loren G.、Young Stephen G.、Nakajima Katsuyuki、Beigneux Anne P.
  • Journal Title: Annals of Internal Medicine Volume: 173 Issue: 9 Pages: 764-765
  • DOI: 10.7326/l20-0327
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Molecular mechanism of triglyceride metabolism. (2022)
  • Author(s): Masami Murakami
  • Organizer: The 31st World Congress of the World Association of Societies of Pathology and Laboratory Medicine
  • Int'l Joint Research / Invited
• [Presentation] Autoimmune hypertriglyceridemia. (2022)
  • Author(s): Masami Murakami
  • Organizer: The 24th International Congress of Clinical Chemistry and Laboratory Medicine
  • Int'l Joint Research / Invited
• [Presentation] Japanese promotion council for laboratory testing (JPCLT), a unique cross-functional organization to promote laboratory medicine in Japan. (2022)
  • Author(s): Masami Murakami
  • Organizer: Laboratory Medicine Congress & Exhibition 2022, Korean Society of Laboratory Medicine 63rd Annual Meeting
  • Int'l Joint Research / Invited
• [Book] 内科学 第12版 (2022)
  • Author(s): 矢﨑 義雄、小室 一成
  • Total Pages: 2572
  • Publisher: 朝倉書店
  • ISBN: 9784254322804