Abstract
Steroid hormones regulate diverse physiological functions such as reproduction, blood salt balance, maintenance of secondary sexual characteristics, response to stress, neuronal function and various metabolic processes. They are synthesized from cholesterol mainly in the adrenal gland and gonads in response to tissue-specific tropic hormones. These steroidogenic tissues are unique in that they require cholesterol not only for membrane biogenesis, maintenance of membrane fluidity and cell signaling, but also as the starting material for the biosynthesis of steroid hormones. It is not surprising, then, that cells of steroidogenic tissues have evolved with multiple pathways to assure the constant supply of cholesterol needed to maintain optimum steroid synthesis. The cholesterol utilized for steroidogenesis is derived from a combination of sources: 1) de novo synthesis in the endoplasmic reticulum (ER); 2) the mobilization of cholesteryl esters (CEs) stored in lipid droplets through cholesteryl ester hydrolase; 3) plasma lipoprotein-derived CEs obtained by either LDL receptor-mediated endocytic and/or SR-BI-mediated selective uptake; and 4) in some cultured cell systems from plasma membrane-associated free cholesterol. Here, we focus on recent insights into the molecules and cellular processes that mediate the uptake of plasma lipoprotein-derived cholesterol, events connected with the intracellular cholesterol processing and the role of crucial proteins that mediate cholesterol transport to mitochondria for its utilization for steroid hormone production. In particular, we discuss the structure and function of SR-BI, the importance of the selective cholesterol transport pathway in providing cholesterol substrate for steroid biosynthesis and the role of two key proteins, StAR and PBR/TSO in facilitating cholesterol delivery to inner mitochondrial membrane sites, where P450scc (CYP11A) is localized and where the conversion of cholesterol to pregnenolone (the common steroid precursor) takes place.
Highlights
Cholesterol is a starting material for the biosynthesis of steroid hormones; these fat soluble, low molecular weight substances play diverse and important physiological functions (Table 1)
Receptor-mediated uptake and internalization of plasma lipoprotein-derived cholesterol (a) LDL(B/E)-receptor-mediated endocytic uptake of LDLcholesterol cellular de novo cholesterol synthesis and cholesteryl esters stored in lipid droplets can potentially supply adequate amounts of cholesterol substrate to support steroidogenesis, the overwhelming evidence suggests that the adrenal and ovary preferentially utilize plasma lipoprotein-derived cholesterol for steroid synthesis [9,20]
We showed that when double tagged-SR-BI proteins (SR-BI-cMyc and SR-BI-V5) are co-expressed in HEK-293 cells and the different proteins are subsequently immunostained and identified with two differently stained gold particles, there is mixing and clustering of gold particles suggesting 1) that the proteins travel to the same cell location, and 2) that many of the gold particles are in exceedingly close physical contact, i.e., within the distance accepted for protein dimers by fluorescent resonance energy transfer (FRET) technique [116,117]
Summary
Cholesterol is a starting material for the biosynthesis of steroid hormones; these fat soluble, low molecular weight substances play diverse and important physiological functions (Table 1). Lipid droplets are associated with proteins involved in vesicle-vesicle targeting and the fusion process in the cells including N-ethylmaleimide (NEM)-sensitive factor (NSF), soluble NSF attachment protein (alpha-SNAP), and the SNAP receptors (SNAREs), synaptosomal-associated protein of 23 kDa (SNAP23), syntaxin-5 and vesicleassociated membrane protein 4 (VAMP4), a chaperone protein that participates in [198] In this context our own studies have shown that treatment of steroidogenic cells with NEM, an inhibitor of NSF, results in a total block of HDL-derived selective cholesteryl ester uptake [72,73]. The TSPO-dependent import of StAR into mitochondria, StAR interaction with VDAC1, and phosphate carrier protein (PCP) on the OMM, and the association of TSPO with the outer/inner mitochondrial membrane contact sites, drives the intramitochondrial cholesterol transfer and subsequent steroid formation [288]
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