Regulation of cholesterol side chain cleavage activity

The cholesterol side chain cleavage enzyme (P450scc) responsible for the initiation of the steroidogenic process is located in the inner membrane of the mitochondria. This inner mitochondrial membrane contains small amounts of cholesterol. The availability of cholesterol in the inner membrane is thus at least one of the rate-limiting factors for the generation of pregnenolone from cholesterol. Other factors that are of importance are the amount of oxygen, the activity of the P450scc enzyme and the capacity for delivering reducing equivalents from NADPH to the P450scc via flavoproteins and iron containing proteins (see Figure 1.2). The capacity of the electron transport system appears not to be rate-limiting for steroid production since more than 10fold higher rates of pregnenolone production can be obtained in Leydig cells when, instead of cholesterol, the more soluble intermediate 22R-hydroxycholesterol is provided. The various steps in the side chain cleavage process i.e. the hydroxylations at C22 and C20 followed by cleavage of the bond between C20 and C22 are catalysed by one enzyme (P450scc). The affinity of the enzyme for the intermediates and the conversion rates are high and no significant amounts of intermediates can be measured in mitochondria. Under normal physiological conditions the generation of steroids from cholesterol mainly depends on the supply of substrate (cholesterol) to the enzyme P450scc and on the amount of P450scc in

cholesterol pregnenolone

The cholesterol side-chain cleavage system in mitochondria.

cholesterol pregnenolone

The cholesterol side-chain cleavage system in mitochondria.

the mitochondria. The amount of the P450scc enzyme is clearly regulated by LH, especially at puberty, but after this induction period the enzyme expression is fairly constant. There are no indications that the P450scc protein can be regulated directly by hormone-dependent phosphorylation. During short-term regulation of steroidogenesis (when the amount of P450scc is constant), the rate-determining step is the transfer of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane that is deficient in cholesterol. For a long time it was known that hormone-controlled intra-mitochondrial cholesterol trafficking was dependent on the presence of one or more proteins with rapid turnover. Several years ago it was shown that the steroidogenesis activator protein (StAR) fulfils the criteria for this labile protein. This does not only hold true for Leydig cells, but applies to all cells in the adrenal and ovary that are active in hormone-dependent synthesis of steroids (Stocco 2001).

The transcription of the StAR gene during embryonal development is regulated by the transcription regulator SF-1, an orphan receptor, which also regulates the expression of the genes for the P450 enzymes (Rice et al. 1991; Clark et al. 1995; Parker and Schimmer 1997). It thus appears that all the essential elements for hormone-dependent steroidogenesis are regulated in a coordinated fashion. The rate of transcription of the StAR gene is controlled by hormones, but under normal conditions there is always enough messenger RNA to sustain a steady state production of a 37 kDa protein precursor. This 37 kDa protein can be transported to the mitochondria where it interacts with proteins on the outer mitochondrial membrane. As a result of transient interactions "contact sites" are formed between the outer and inner mitochondrial membrane. These bridges allow cholesterol transfer from the outer membrane to the inner membrane. Since StAR is continuously processed and inactivated, persistent synthesis and probably also hormone-dependent phosphorylation of StAR are required to maintain hormone activated steroid production.

A very important observation in favour of the important role of StAR in the control of steroidogenesis came from studies on the disease lipoid congenital adrenal hyperplasia. This disease is characterised by an accumulation of cholesterol within Leydig cells and adrenal cells and an inability of the patients to synthesize enough steroids. It could be shown that mutations in the StAR gene which caused truncation and inactivation of the StAR protein were the cause of this disease (Stocco 2002). These clinical data further support the physiological importance of StAR for activated steroid production. However, it is known that limited amounts of steroids can also be produced in tissues without StAR, such as the placenta Although the production per cell is limited, together the many cells of the placenta can produce substantial amounts of steroids. Also Leydig cells in StAR knockout mice retain some capacity for androgen synthesis without the possibility for rapid hormonal regulation (Hasegawa etal. 2000). These observations indicate that other proteins, such as the peripheral type of the benzodiazepine receptor in the mitochondria, can also assist in cholesterol transport (Papadopoulos 1993). However, it is now firmly established that StAR is essential for the rapid regulation of steroid production.

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