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Hormonal Regulation of Testicular Steroid and Cholesterol Homeostasis

Department of Genome Sciences (S.M.E., R.E.B.) and Division of Endocrinology (N.A., K.Q., H.L.D.), Department of Pediatrics, University of Washington, Seattle, Washington 98195; and School of Biological Sciences and Technology (E.-Y.G., K.L.), Hormone Research Center, Chonnam National University, Gwangju 500-757, Republic of Korea

Address all correspondence and requests for reprints to: Robert E. Braun, Department of Genome Sciences, University of Washington, Seattle, Washington 98195. E-mail: Bob.braun{at}jax.org.

The male sex steroid, testosterone (T), is synthesized from cholesterol in the testicular Leydig cell under control of the pituitary gonadotropin LH. Unlike most cells that use cholesterol primarily for membrane synthesis, steroidogenic cells have additional requirements for cholesterol, because it is the essential precursor for all steroid hormones. Little is known about how Leydig cells satisfy their specialized cholesterol requirements for steroid synthesis. We show that in mice with a unique hypomorphic androgen mutation, which disrupts the feedback loop governing T synthesis, that genes involved in cholesterol biosynthesis/uptake and steroid biosynthesis are up-regulated. We identify LH as the central regulatory molecule that controls both steroidogenesis and Leydig cell cholesterol homeostasis in vivo. In addition to the primary defect caused by high levels of LH, absence of T signaling exacerbates the lipid homeostasis defect in Leydig cells by eliminating a short feedback loop. We show that T signaling can affect the synthesis of steroids and modulates the expression of genes involved in de novo cholesterol synthesis. Surprisingly, accumulation of active sterol response element-binding protein 2 is not required for up-regulation of genes involved in cholesterol biosynthesis and uptake in Leydig cells.