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

Gamma 3-melanotropin (γ₃-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 γ₃-MSH are potent, while γ-MSH is not. This cholesterol accumulation coincides with the activation of cholesteryl ester hydrolysis by γ₃-MSH, while the rates of cholesterol esterification and of mitochondrial cholesterol side-chain cleavage are unaffected. Conversely, ACTH inhibits cholesterol esterification. Therefore, γ₃-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 γ₃-MSH. These data extend our previous studies demonstrating that pro-y-MSH polypeptides have an endocrine influence on the rat adrenal cortex.