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Aberrant Cholesterol Transport and Impaired Steroidogenesis in Leydig Cells Lacking Estrogen Sulfotransferase

Center for Experimental Therapeutics (M.H.T., W.-C.S.), Department of Pharmacology (W.C.S.), and Center for Research on Reproduction and Women’s Health (L.K.C.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: W. C. Song, Ph.D., University of Pennsylvania School of Medicine, Room 1351 BRBII/III, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104. E-mail: song{at}spirit.gcrc.upenn.edu.

Estrogen sulfotransferase (EST) is a cytosolic enzyme that catalyzes the sulfoconjugation and inactivation of estrogens. It is expressed abundantly in the mammalian testes in which it may modulate the activity of locally produced estrogen. We demonstrate here that testicular Leydig cells from mice rendered deficient in EST expression by targeted gene deletion acquire a phenotype of increased cholesterol ester accumulation and impaired steroidogenesis with natural aging or in response to estrogen challenge. Abnormal accumulation of cholesterol ester in the mutant Leydig cells correlated with induced expression of the scavenger receptor type B class I, and cultured EST-deficient but not wild-type Leydig cells avidly uptook high-density lipoprotein cholesterol ester ex vivo. EST-deficient Leydig cells in culture produced 50–70% less testosterone than wild-type cells. This deficiency was reversed by androstenedione but not progesterone supplementation, indicating that reduced activities of 17--hydroxylase-17, 20-lyase were responsible. This conclusion was corroborated by decreased expression levels of 17--hydroxylase-17, 20-lyase but not of other key steroidogenic enzymes in the mutant cells. These results suggest that EST plays a physiologic role in protecting Leydig cells from estrogen-induced biochemical lesions and provide an example of critical regulation of tissue estrogen sensitivity by a ligand-transformation enzyme rather than through estrogen receptors.

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