Autophagy regulates testosterone synthesis by facilitating cholesterol uptake in Leydig cells

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Animals
  • Autophagy* / drug effects
  • Autophagy-Related Proteins / metabolism
  • CD36 Antigens / metabolism
  • Cholesterol / metabolism*
  • Chorionic Gonadotropin / pharmacology
  • Down-Regulation / drug effects
  • Humans
  • Leydig Cells / cytology*
  • Leydig Cells / drug effects
  • Leydig Cells / metabolism*
  • Male
  • Mice
  • Models, Biological
  • Phosphoproteins / chemistry
  • Phosphoproteins / metabolism
  • Sexual Behavior, Animal / drug effects
  • Sodium-Hydrogen Exchangers / chemistry
  • Sodium-Hydrogen Exchangers / metabolism
  • Testosterone / biosynthesis*
  • Testosterone / blood
  • Young Adult


  • Autophagy-Related Proteins
  • CD36 Antigens
  • Chorionic Gonadotropin
  • Phosphoproteins
  • Sodium-Hydrogen Exchangers
  • sodium-hydrogen exchanger regulatory factor
  • Testosterone
  • Cholesterol