PrPC Promotes Endometriosis Progression by Reprogramming Cholesterol Metabolism and Estrogen Biosynthesis of Endometrial Stromal Cells through PPARα Pathway

Endometriosis (EMs) is characterized as an estrogen-dependent disease. Whereas, the underlying mechanism for activated estrogen biosynthesis in EMs lesions is largely unknown. We analyzed cholesterol metabolism and estrogen biosynthesis condition of EMs lesions by biological information analysis of GEO datasets, and further verified both in vitro and in vivo by constructing EMs models with uterus fragments from donors of PRNP knockout mouse (Prnp(-/-), KO119), Octapeptide repeat region of PRNP knockout mouse (KO120) and PRNP transgenic mouse (Tg20). We found that transcriptome of cholesterol metabolism and estrogen-converting enzymes were disturbed in EMs patients, and cellular cholesterol concentration and local estradiol level were substantially increased in EMs lesions, as well as the high level of prion (PrPC, encoded by PRNP). Notably, 17-beta estradiol stimulation significantly up-regulated PrPC expression in endometrial stromal cells (ESC) and PrPC promoted the proliferative, migratory and invasive abilities of ESC, and was further verified to accelerate EMs progression in mouse models. More importantly, PrPC promoted cholesterol accumulation and activated estrogen biosynthesis of ESC in a PPAR alpha pathway-dependent manner. Taken together, this study suggests that PrPC-cholesterol metabolism/estrogen biosynthesis contributes to the progression of EMs by negatively regulating PPAR alpha pathway, and could be potential therapeutic targets for EMs intervention.

Automated summary

The study reveals that disturbed cholesterol metabolism and estrogen-converting enzymes in EMs lesions lead to increased cellular cholesterol concentration and local estradiol level. PrPC promotes the proliferative, migratory, and invasive abilities of ESC in endometrial stromal cells and accelerates EMs progression in mouse models. Furthermore, PrPC promotes cholesterol accumulation and activates estrogen biosynthesis of ESC in a PPAR alpha pathway-dependent manner, suggesting potential therapeutic targets for EMs intervention.