Elucidation of the pathophysiology of steroid hormone biosynthesis in lipoid congenital adrenal hyperplasia by establishing a mouse or cell line model

• Project/Area Number: 16K09996
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Keio University
• Principal Investigator: Ishii Tomohiro 慶應義塾大学, 医学部(信濃町), 准教授 (70265867)
• Research Collaborator: MIZUNO Yusuke ; SATO Takeshi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: StAR / 先天性リポイド副腎過形成症 / ステロイドホルモン生合成 / コレステロール / STAR / Star / トランスレーショナルリサーチ / 脂質 / 生理学 / 遺伝子 / 遺伝学

Outline of Final Research Achievements

The present study developed significant progress in the understanding pathophysiology of lipoid congenital adrenal hyperplasia (LCAH). First, the study successfully established steroidogenic cell lines lacking steroidogenic acute regulatory protein (StAR) and tamoxifen-inducible knockout mice lacking StAR as in vitro and in vivo models for LCAH, respectively. Second, the results of the study demonstrated the presence of StAR-independent steroidogenic pathway, the role of cAMP in the pathway, and the impairment of the pathway secondary to the accumulation of cholesterol esters in the cytosol of adrenocortical cells. Third, the study indicates that the impairment of StAR-independent steroidogenic pathway secondary to the accumulation of cholesterol esters is associated with global reduction of expression levels of genes related to steroidogenesis probably due to reduced expression of NR5A1.

Academic Significance and Societal Importance of the Research Achievements

Steroidogenic acute regulatory protein（StAR）を欠損したステロイドホルモン産生細胞株、タモキシフェン投与でStARを欠損するマウスを作成して、先天性リポイド副腎過形成症（LCAH）の病態モデルを細胞とマウスの双方で確立した研究は国内外で初めてである。コレステロールエステル蓄積により二次的に障害されるStAR非依存性のステロイドホルモン産生経路を保持する手段が開発されれば、LCAH女性患者の卵巣機能を維持する新たな治療法への発展が期待される。

Research Products

• [Journal Article] In vivo Verification of the Pathophysiology of Lipoid Congenital Adrenal Hyperplasia in the Adrenal Cortex (2018)
  • Author(s): Yusuke Mizuno、Tomohiro Ishii 、Tomonobu Hasegawa
  • Journal Title: Endocrinology Volume: 160 Issue: 2 Pages: 331-338
  • DOI: 10.1210/en.2018-00777
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pubertal Development and Pregnancy Outcomes in 46,XX Patients with Nonclassic Lipoid Congenital Adrenal Hyperplasia. (2018)
  • Author(s): Hatabu N, Amano N, Mori J, Hasegawa Y, Matsuura H, Sumitomo N, Nishizawa K, Suzuki M, Katakura S, Kanamoto N, Kamimaki T, Ishii T, Hasegawa T
  • Journal Title: J Clin Endocrinol Metab Volume: ePub ahead Issue: 5 Pages: 1866-1870
  • DOI: 10.1210/jc.2018-01752
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic Defects in Pediatric-onset Adrenal Insufficiency in Japan (2017)
  • Author(s): Amano N, Narumi S, Hayashi M, Takagi M, Imai K, Nakamura T, Hachiya R, Sasaki G, Homma K, Ishii T, Hasegawa T
  • Journal Title: Eur J Endocrinol Volume: 177 Issue: 2 Pages: 187-194
  • DOI: 10.1530/eje-17-0027
  • Peer Reviewed
• [Journal Article] A novel case of somatic KCNJ5 mutation in pediatric-onset aldosterone- producing adenoma (2017)
  • Author(s): Uchida N, Amano N, Yamaoka Y, Uematsu A, Sekine Y, Suzuki M, Watanabe J, Nishimoto K, Mukai K, Fukuzawa R, Hasegawa T, Ishii T
  • Journal Title: J Endocrine Soc Volume: 1 Issue: 8 Pages: 1056-1061
  • DOI: 10.1210/js.2017-00210
  • Peer Reviewed / Open Access
• [Presentation] In vivo confirmation of a two-hit hypothesis in the pathophysiology of lipoid congenital adrenal hyperplasia in the adrenal cortexes (2018)
  • Author(s): Yusuke Mizuno、Tomohiro Ishii 、Tomonobu Hasegawa
  • Organizer: The 18th Adrenal Cortex Conference
  • Int'l Joint Research
• [Presentation] リポイド副腎過形成症の副腎における二次的なステロイド産生能低下の病態解明 (2018)
  • Author(s): 水野 裕介、石井 智弘、長谷川 奉延
  • Organizer: 第52回日本小児内分泌学会
• [Presentation] Recent Advances in Pediatric Adrenal Disorders (2016)
  • Author(s): Tomohiro Ishii
  • Organizer: The 39th symposium of the Korean Society of Pediatric Endocrinology meetingｓ
  • Place of Presentation: Gangchon, South Korea
  • Int'l Joint Research / Invited