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J Cell Biol. 2018 Jun 4;217(6):2103-2119. doi: 10.1083/jcb.201710078. Epub 2018 Apr 4.

Autophagy regulates testosterone synthesis by facilitating cholesterol uptake in Leydig cells.

Gao F1,2, Li G3, Liu C1, Gao H1, Wang H4, Liu W1, Chen M1, Shang Y1,5, Wang L1,5, Shi J1,5, Xia W1,5, Jiao J1, Gao F1, Li J3, Chen L6, Li W7,5.

Author information

1
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
2
School of Biotechnology and Food, Shangqiu Normal University, Shangqiu, China.
3
The Ministry of Health Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China.
4
Reproductive and Genetic Medical Center, Department of Urology, Peking University First Hospital, Beijing, China.
5
College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
6
Reproductive and Genetic Medical Center, Department of Urology, Peking University First Hospital, Beijing, China bdyychenliang@163.com.
7
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China leways@ioz.ac.cn.

Abstract

Testosterone is indispensable for sexual development and maintaining male characteristics, and deficiency of this hormone results in primary or late-onset hypogonadism (LOH). Testosterone is primarily produced in Leydig cells, where autophagy has been reported to be extremely active. However, the functional role of autophagy in testosterone synthesis remains unknown. In this study, we show that steroidogenic cell-specific disruption of autophagy influenced the sexual behavior of aging male mice because of a reduction in serum testosterone, which is similar to the symptoms of LOH. The decline in testosterone was caused mainly by a defect in cholesterol uptake in autophagy-deficient Leydig cells. Further studies revealed that once autophagic flux was disrupted, Na+/H+ exchanger regulatory factor 2 (NHERF2) accumulated in Leydig cells, resulting in the down-regulation of scavenger receptor class B, type I (SR-BI) and eventually leading to insufficient cholesterol supply. Collectively, these results reveal that autophagy promotes cholesterol uptake into Leydig cells by eliminating NHERF2, suggesting that dysfunction of autophagy might be causal in the loss of testosterone production in some patients.

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