Relationship of Star Expression to Mitochondrial Cholesterol Transfer and Metabolism

Experiments in Y-1 and primary adrenal cells have established that basal StAR mRNA is sufficient for maximum cAMP-stimulated cholesterol metabolism providing that newly synthesized p37 StAR precursor is phosphorylated, transferred to the matrix and proteolytically cleaved to pp30. This form is active at the inner membrane. The majority of mitochondrial StAR redistributes, perhaps with cholesterol, to matrix vesicles but no longer facilitates intermembrane transfer even when appropriately phosphorylated. MA10 cells utilize a similar to Y01 cells mechanism, but sustain a higher rate of cholesterol metabolism at comparable StAR levels and exhibit much higher maximum rates. In Y-1 adrenal cells cholesterol metabolism is fully activated prior to increased StAR expression which then does not affect the rate. Thus factors other than StAR are at least as important in determining overall rates of cholesterol delivery. Following cAMP stimulation StAR is predominantly expressed as the 3.5kb form which arises from alternative polyadenylation following transcription of an extended exon 7. This form contains an AU-rich regulatory element at the 3′-end that potentially mediates the relatively rapid turnover of this form. The 1.6kb form is more stable and reaches a steady state at later time points. Turnover of both forms is coupled tightly to ongoing transcription and translation. In addition to enhanced transcription cAMP appears to direct enhanced turnover of the 3.5kb form. StAR participation in cholesterol metabolism functions at very low levels of mRNA and high efficiency at each step.