Amodiaquine promotes testosterone production and de novo synthesis of cholesterol and triglycerides in Leydig cells
- 주제(키워드) amodiaquine , cholesterol synthesis , lipidomics , steroidogenesis , steroidogenic
- 주제(기타) Biochemistry & Molecular Biology
- 설명문(일반) [Choi, Yujeong; Lee, Gibbeum; Jeong, Mi Gyeong; Kim, Hyo Kyeong; Oh, Ji-Hyun; Hwang, Eun Sook] Ewha Womans Univ, Coll Pharm, Seoul, South Korea; [Choi, Yujeong; Lee, Gibbeum; Jeong, Mi Gyeong; Kim, Hyo Kyeong; Oh, Ji-Hyun; Hwang, Eun Sook] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Seoul, South Korea; [Lee, Eun Goo; Kwon, Sung Won] Seoul Natl Univ, Dept Pharm, Seoul, South Korea; [Lee, Eun Goo; Kwon, Sung Won] Seoul Natl Univ, Coll Pharm, Seoul, South Korea
- 등재 SCIE, SCOPUS
- OA유형 Green Published, gold
- 발행기관 ELSEVIER
- 발행년도 2021
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000190437
- 본문언어 영어
- Published As https://doi.org/10.1016/j.jlr.2021.100152
- PubMed https://pubmed.ncbi.nlm.nih.gov/34808194
초록/요약
Testosterone is a hormone essential for male reproductive function. It is produced primarily by Leydig cells in the testicle through activation of steroidogenic acute regulatory protein and a series of steroidogenic enzymes, including a cytochrome P450 side-chain cleavage enzyme (cytochome P450 family 11 subfamily A member 1), 17 alpha-hydroxylase (cyto-chrome P450 family 17 subfamily A member 1), and 30-hydroxysteroid dehydrogenase. These steroido-genic enzymes are mainly regulated at the transcrip-tional level, and their expression is increased by the nuclear receptor 4A1. However, the effect on Leydig cell function of a small molecule-activating ligand, amodiaquine (AQ), is unknown. We found that AQ effectively and significantly increased testosterone production in TM3 and primary Leydig cells through enhanced expression of steroidogenic acute regula-tory protein, cytochome P450 family 11 subfamily A member 1, cytochrome P450 family 17 subfamily A member 1, and 30-hydroxysteroid dehydrogenase. Concurrently, AQ dose-dependently increased the expression of 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in the cholesterol synthesis pathway, through induction of the transcriptional and DNA-binding activities of nuclear receptor 4A1, contributing to increased cholesterol synthesis in Leydig cells. Furthermore, AQ increased the expres-sion of fatty acid synthase and diacylglycerol acyl-transferase and potentiated de novo synthesis of fatty acids and triglycerides (TGs). Lipidomics profiling further confirmed a significant elevation of intra-cellular lipid and TG levels by AQ in Leydig cells. These results demonstrated that AQ effectively pro-motes testosterone production and de novo synthesis of cholesterol and TG in Leydig cells, indicating that AQ may be beneficial for treating patients with Ley-dig cell dysfunction and subsequent testosterone deficiency.
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