Steroidogenic acute regulatory protein

The steroidogenic acute regulatory protein, commonly referred to as StAR (STARD1), is a

The mechanism by which StAR causes cholesterol movement remains unclear as it appears to act from the outside of the mitochondria and its entry into the mitochondria ends its function. Various hypotheses have been advanced. Some involve StAR transferring cholesterol itself like a shuttle.[1]^[2] While StAR may bind cholesterol itself,^[3] the exorbitant number of cholesterol molecules that the protein transfers would indicate that it would have to act as a cholesterol channel instead of a shuttle. Another notion is that it causes cholesterol to be kicked out of the outer membrane to the inner (cholesterol desorption).^[4] StAR may also promote the formation of contact sites between the outer and inner mitochondrial membranes to allow cholesterol influx. Another suggests that StAR acts in conjunction with PBR, causing the movement of Cl⁻ out of the mitochondria to facilitate contact site formation. However, evidence for an interaction between StAR and PBR remains elusive.

Structure

In humans, the gene for StAR is located on chromosome 8p11.23^[5] and the protein has 285 amino acids. The signal sequence of StAR that targets it to the mitochondria is clipped off in two steps with import into the mitochondria. Phosphorylation at the serine at position 195 increases its activity.^[6]

The domain of StAR important for promoting cholesterol transfer is the

The closest

At the cellular level, StAR is synthesized typically in response to activation of the cAMP second messenger system, although other systems can be involved even independently of cAMP.^[9]

StAR has thus far been found in all tissues that can produce steroids, including the

Substances that suppress StAR activity, like those listed below, can cause endocrine disrupting effects, including altered steroid hormone levels and fertility.

1. Alcohol^[11]
2. DEHP^[12] and DBP^[13]
3. Permethrin^[14] and cypermethrin^[15]
4. DES and arsenite^[16]
5. BPA

Pathology

While loss of functional StAR in the human and the mouse catastrophically reduces steroid production, it does not eliminate all of it, indicating the existence of StAR-independent pathways for steroid generation. Aside from the human placenta, these pathways are considered minor for endocrine production.

It is unclear what factors catalyze StAR-independent steroidogenesis. Candidates include

New roles

Recent findings suggest that StAR may also traffic cholesterol to a second mitochondrial enzyme,

Evidence also shows that the presence of StAR in a type of immune cell, the macrophage, where it can stimulate the production of 27-hydroxycholesterol.^[21][22] In this case, 27-hydroxycholesterol may by itself be helpful against the production of inflammatory factors associated with cardiovascular disease. It is important to note that no study has yet found a link between the loss of StAR and problems in bile acid production or increased risk for cardiovascular disease.

Recently StAR was found to be expressed in cardiac fibroblasts in response to ischemic injury due to myocardial infarction. In these cells it has no apparent de novo steroidogenic activity, as evidenced by the lack of the key steroidogenic enzymes cytochrome P450 side chain cleavage (CYP11A1) and 3 beta hydroxysteroid dehydrogenase (3βHSD). StAR was found to have an anti-apoptotic effect on the fibroblasts, which may allow them to survive the initial stress of the infarct, differentiate and function in tissue repair at the infarction site.^[23]

History

The StAR protein was first identified, characterized and named by Douglas Stocco at Texas Tech University Health Sciences Center in 1994.^[24] The role of this protein in lipoid CAH was confirmed the following year in collaboration with Walter Miller at the University of California, San Francisco.^[25] All of this work follows the initial observations of the appearance of this protein and its phosphorylated form coincident with factors that caused steroid production by Nanette Orme-Johnson while at Tufts University.^[26]

See also

• Steroidogenic enzyme

References