Hepatic KLF9 Deficiency Inhibits Dehydroepiandrosterone (DHEA)-Induced Polycystic Ovary Syndrome via Liver-Ovary Axis.

Abstract

Hyperandrogenism is one of the key leading causes of polycystic ovary syndrome (PCOS), which is a complex metabolic disorder affecting 6% to 20% of women of reproductive age. However, the molecular pathogenetic mechanisms responsible for androgen excess in PCOS remain largely unknow. While most previous studies have specifically focused on ovarian tissue, few have evaluated the role of extraovarian organs in PCOS. Here, it is found that KLF9 expression is up-regulated in murine primary hepatocytes treated with DHEA. Notably, the genetic ablation of Klf9 in hepatocytes significantly alleviated the progression of DHEA induced PCOS in mouse. Conversely, hepatic Klf9 transgenic mice displayed a spontaneous PCOS-like phenotype. Mechanistically, hepatic KLF9 is directly activated by intranuclear AR and then directly binds to the promoter of Srd5a1 and the gene loci of Hsd3b3, which encode the enzyme for the conversion of DHEA to dihydrotestosterone, to promote its transcription in the liver. Overall, our study indicated that the liver plays a vital role in the development of PCOS and that hepatic KLF9 might be a potential therapeutic target for PCOS.