Autophagy regulates sex steroid hormone synthesis through lysosomal degradation of lipid droplets in human ovary and testis.
Yashar EsmaeilianFrancesko HelaGamze BildikEce İltumurSevgi YusufogluCeren Sultan YildizKayhan YakinYakup KordanOzgur OktemPublished in: Cell death & disease (2023)
Autophagy is an evolutionarily conserved process that aims to maintain the energy homeostasis of the cell by recycling long-lived proteins and organelles. Previous studies documented the role of autophagy in sex steroid hormone biosynthesis in different animal models and human testis. Here we demonstrate in this study that sex steroid hormones estrogen and progesterone are produced through the same autophagy-mediated mechanism in the human ovary in addition to the human testis. In brief, pharmacological inhibition and genetic interruption of autophagy through silencing of autophagy genes (Beclin1 and ATG5) via siRNA and shRNA technologies significantly reduced basal and gonadotropin-stimulated estradiol (E 2 ), progesterone (P 4 ) and testosterone (T) production in the ex vivo explant tissue culture of ovary and testis and primary and immortalized granulosa cells. Consistent with the findings of the previous works, we observed that lipophagy, a special form of autophagy, mediates the association of the lipid droplets (LD)s with lysosome to deliver the lipid cargo within the LDs to lysosomes for degradation in order to release free cholesterol required for steroid synthesis. Gonadotropin hormones are likely to augment the production of sex steroid hormones by upregulating the expression of autophagy genes, accelerating autophagic flux and promoting the association of LDs with autophagosome and lysosome. Moreover, we detected some aberrations at different steps of lipophagy-mediated P 4 production in the luteinized GCs of women with defective ovarian luteal function. The progression of autophagy and the fusion of the LDs with lysosome are markedly defective, along with reduced P 4 production in these patients. Our data, together with the findings of the previous works, may have significant clinical implications by opening a new avenue in understanding and treatment of a wide range of diseases, from reproductive disorders to sex steroid-producing neoplasms, sex steroid-dependent malignancies (breast, endometrium, prostate) and benign disorders (endometriosis).
Keyphrases
- low density lipoprotein
- cell death
- endoplasmic reticulum stress
- signaling pathway
- oxidative stress
- endothelial cells
- induced apoptosis
- cell cycle arrest
- prostate cancer
- induced pluripotent stem cells
- type diabetes
- fatty acid
- fluorescent probe
- adipose tissue
- genome wide
- pluripotent stem cells
- transcription factor
- single cell
- dna methylation
- end stage renal disease
- metabolic syndrome
- gene expression
- estrogen receptor
- insulin resistance
- cell proliferation
- skeletal muscle
- peritoneal dialysis
- machine learning
- chronic kidney disease
- artificial intelligence
- polycystic ovary syndrome
- living cells
- drug delivery
- ejection fraction