Clinical disorders associated with abnormal cholesterol transport: mutations in the steroidogenic acute regulatory...

The transport of cholesterol to the inner mitochondrial membrane of steroidogenic cells constitutes the rate-limiting step in trophic hormone regulated steroid biosynthesis and requires de novo protein synthesis. Several years ago a candidate regulator protein was purified and its cDNA cloned from MA-10 mouse Leydig tumor cells. Expression of this protein resulted in an increase in steroidogenesis in unstimulated cells and it was named the Steroidogenic Acute Regulatory protein or StAR. Mutations in the StAR gene were found to be the cause of the potentially lethal disease in humans known as congenital lipoid adrenal hyperplasia (lipoid CAH), a condition characterized by an almost complete inability of the newborn to synthesize steroids. The defect in steroid synthesis in lipoid CAH is caused by the failure of affected individuals to transport cholesterol to the inner mitochondria membrane, thus proving the essential role of StAR in cholesterol transport. StAR null mice display a phenotype that is essentially identical to the human condition. In summary, both naturally occurring disorders in humans and genetic manipulation in mice have demonstrated that the StAR protein is an absolute requirement in the rate-limiting step in steroidogenesis, the transfer of cholesterol into the mitochondria.