Apolipoprotein E is a putative autocrine regulator of the rat ovarian theca cell compartment

Apolipoprotein (apo) E inhibits androgen production by ovarian theca cells. We found that apo E, as a synthetic peptide mimicked the full-size protein , induced theca and interstitial cell (TIC) apoptosis indicated by pyknotic cell morphology, increased DNA end-labeling (TUNEL), and DNA ladders. None of the low-density lipoprotein (LDL) receptor superfamily members were inv olved because the universal antagonist of these receptors, receptor-associa ted protein (RAP), did not block apo E-induced apoptosis. Furthermore, seve ral apo E synthetic peptides that do not bind the LDL receptor did induce T IC apoptosis. Similar to apo E, apoptogenic agents such as ceramide and LY 294002, a phosphatidylinositol (PI) 3-kinase inhibitor, induced apoptosis a nd suppressed androstenedione production. However, apoptosis alone was not responsible for apo E suppression of androstenedione production because bot h insulin and IGF-I prevented apo E-induced apoptosis, but neither restored androstenedione production. Theca cells of atretic follicles express the g reatest apo E mRNA, and here we show that cultured TIC produce apo E. When considered with the observation of TUNEL-positive theca cells in atretic fo llicles these results support our hypothesis that intraovarian apo E contro ls theca cell production of androgen as well as limiting the size of the th eca cell compartment.