Discovery of autophagy as a universal mechanism for sex steroid synthesis in human ovary and testis.

Abstract

We recently discovered that lipophagy is a key mechanism to provide free cholesterol required for steroid biosynthesis in human ovary and testis. Pharmacological or genetic inhibition of autophagy by silencing of the autophagy-related (ATG) genes BECN1 (BECLIN1) and ATG5 resulted in a significant reduction in basal and gonadotropin-stimulated estradiol, progesterone (P₄) and testosterone production in the ex-vivo explant tissue and cell culture models for ovary and testis. We also described a new mechanism of action for gonadotropin hormones, i.e., follicle stimulating hormone (FSH) and human chorionic gonadotropin (hCG)/luteinizing hormone (LH), in this process. They augment the production of sex steroid hormones by upregulating the expression of ATG genes, the accelerating autophagic flux and promoting LDs sequestration into autophagosomes and degradation in lysosomes. Furthermore, we detected several molecular aberrations at different steps of lipophagy-dependent P₄ production in the ovary of women with defective luteal function. Our findings might have important clinical implications by opening a new avenue for the understanding and treatment of a wide range of diseases varying from reproductive disorders to sex hormone-producing neoplasms and hormone dependent malignancies, such as carcinomas of breast, endometrium, and prostate. Abbreviations: ACAT, Acyl-coenzyme A-cholesterol-acyl-transferase; AMBRA1, autophagy and beclin 1 regulator 1; ATG, autophagy-related; BECN1, BECLIN1; hCG, human chorionic gonadotropin; E_2, estradiol; FSH, follicle stimulating hormone; GABARAP, GABA type A receptor-associated protein; GCs, luteinized granulosa cells; IVF, in vitro fertilization; LAMP2A, lysosomal associated membrane protein 2A; LDs, lipid droplets; LDLs, low-density lipoproteins; P₄: progesterone; PCOS, polycystic ovary syndrome; SOAT1: Sterol-O-acetyltransferase; MAP1LC3B, microtubule associated protein 1 light chain 3 beta; PLIN3, perilipin 3; STAR, steroidogenic acute regulatory protein; SQSTM1, sequestosome-1.