Gamma 3-melanotropin promotes mitochondrial cholesterol accumulation in the rat adrenal cortex

Gamma 3-melanotropin (gamma 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 gamma 3-MSH are potent, while gamma-MSH is not. This cholesterol accumulation coincides with the activation of cholesteryl ester hydrolysis by gamma 3-MSH, while the rates of cholesterol esterification and of mitochondrial cholesterol side-chain cleavage are unaffected. Conversely, ACTH inhibits cholesterol ester esterification. Therefore, gamma 3-MSH and ACTH together may coordinate a substantial shift in the set-point of cholesteryl ester in equilibrium 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 gamma 3-MSH. These data extend our previous studies demonstrating that pro-gamma-MSH polypeptides have an endocrine influence on the rat adrenal cortex.