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Polyphosphoinositides: Stimulator of Mitochondrial Cholesterol Side Chain Cleavage and Possible Identification as an Adrenocorticotropin-Induced, Cycloheximide-Sensitive, Cytosolic, Steroidogenic Factor^*

Veterans Administration Hospital and the Department of Medicine, University of South Florida College of Medicine Tampa, Florida 33612

Address requests for reprints to: Dr. Robert V. Farese, Division of Endocrinology and Metabolism, College of Medicine, Box 19, Tampa, Florida 33612.

Abstract

ACTH treatment in vivo enhances the activity of adrenal cytosol for supporting pregnenolone synthesis in adrenal mitochondria. Upon fractionation of adrenal cytosol by gel filtration through Sephadex G200, pregnenolone synthesisstimulating activity is eluted just after ³H₂O(K_d = 1.1–2.1). This late eluting steroidogenic activity is enhanced by ACTH treatment and diminished by cycloheximide treatment, which also inhibits adrenal protein synthesis and ACTH-induced steroidogenesis. Chromatography on Sephadex G-10 yields even further separation of steroidogenic factor(s) from inactive substances; it appears that the active factor(s) adsorbs to Sephadex and that such adsorption is enhanced by a greater degree of cross-linking in the gel. The phospholipids, cardiolipin, diphosphoinositide, and triphosphoinositide, are recovered partly in adrenal cytosol and, by virtue of their polyphosphorylated head group, specifically stimulate mitochondrial pregnenolone synthesis. It seems likely that the ACTH effect on cytosolic steroidogenic activity is due to changes in polyphosphoinositides, since these phospholipids are specifically stimulated by ACTH, cycloheximide blocks the ACTH-induced increase in polyphosphoinositides, and these phospholipids comigrate with steroidogenic activity during gel filtration of adrenal cytosol. These findings along with other findings from our laboratory suggest that polyphosphoinositides may function as a cycloheximide-sensitive mediator in the steroidogenic action of ACTH. (Endocrinology 106: 1869, 1980)

Footnotes

^* This work was supported by funds from the Research Service of the V.A. Presented in part at the 61st Annual Meeting of The Endocrine Society, Anaheim, CA, 1979.

Received June 7, 1979.