Gamma3-melanotropin promotes mitochondrial cholesterol accumulation in the rat adrenal cortex

Abstract Gamma 3-melanotropin (γ 3 -MSH) facilitates a rapid, dose-dependent, and cycloheximide-insensitive increase in the concentration of mitochondrial free cholesterol in the adrenals of hypophysectomized rats. Physiological concentrations of various synthetic and native preparations of γ 3 -MSH are potent, while γ-MSH is not. This cholesterol accumulation coincides with the activation of cholesteryl ester hydrolysis by γ 3 -MSH, while the rates of cholesterol esterification and of mitochondrial cholesterol side-chain cleavage are unaffected. Conversely, ACTH inhibits cholesterol esterification. Therefore, γ 3 -MSH and ACTH together may coordinate a substantial shift in the set-point of cholesteryl ester ag cholesterol cycling toward the right. Because ACTH also activates cholesterol side-chain cleavage, this coordinate effect on the flux of cholesterol substrate is manifest as a potentiation of Corticosteroidogenesis by γ 3 -MSH. These data extend our previous studies demonstrating that pro-y-MSH polypeptides have an endocrine influence on the rat adrenal cortex.