**3. Capture and processing of cholesterol**

Cells synthesizing steroid hormones (steroidogenic cells) use several pathways that ensure the constant supply of cholesterol for steroid hormone synthesis, including:


The incorporation of lipoproteins into the cells is mediated by a receptor-endocytic mechanism that delivers the lipoproteins to the lysosomes where apolipoproteins are degraded. High density lipoproteins (HDL) are incorporated by the scavenger receptor class B, type I (SR-BI)-mediated selective uptake. Depending on the cell, the synthesis of lipoprotein receptors is stimulated by the adreno-corticotropin-hormone (ACTH) and luteinizing hormone (LH). The source of cholesterol for steroidogenesis varies according to the animal studied (Azhar et al., 2003; Hu et al., 2011). SR-BI synthesis in adrenal cells is stimulated by ACTH and inhibited by glucocorticoids (Mavridou et al., 2010).

The membrane-bound transcription factor sterol regulatory element binding protein (SREBP) is the main regulator for cholesterol synthesis and cellular uptake. In mammalian cells, protein Insig, an endoplasmic- reticulum membrane protein, controls the activity of SREBP and the sterol-dependent degradation of the biosynthetic enzyme HMG-CoA reductase (Espenshade & Hughes 2007).

The cholesterol side chain cleavage reaction is the first step, and also the rate-limiting process in steroid hormone synthesis. The reaction takes place on the inner mitochondrial membranes and is catalyzed by the cholesterol-side-chain cleavage enzyme, cytochrome P-450scc; Cyp11a1 (Straus & Hsue, 2000). The translocator protein (TSPO) and the steroidogenic acute regulatory (StAR) protein mediate this transfer. TSPO is a high-affinity cholesterol-binding mitochondrial protein and StAR is a hormone-induced mitochondria protein that initiates the transfer of cholesterol into the mitochondria (Hu et al., 2010). In *vitro* studies show that treating Leydig cells with testosterone decreases the expression of SR-BI, TSPO, StAR and cytochrome P-450scc (Kostic et al., 2011). In the adrenals, ACTH induces StAR synthesis by stimulating the synthesis of cyclic adenosin mono phosphate (cAMP), while the early steps in steroidogenic synthesis are mediated by posttranscriptional and post-translational changes in the StAR protein (Spiga et al., 2011). In the gonads, gonadotropic hormones transcriptionally control StAR gene expression via a cAMP second messenger (Sugawara et al., 1997). A characteristic feature of steroidogenic cells is the presence of numerous cytoplasmic lipid droplets containing cholesterol esters. Cholesterol esters in these droplets are synthesized by acyl coenzymeA-cholesterol acyltransferase, an endoplasmic reticulum-enzyme. The esters synthesized by cholesterol acyltransferase accumulate within the endoplasmic reticulum membranes and bud off as lipid droplets. Cholesterol esters in lipid droplets are hydrolyzed by a soluble sterol ester hydrolase. Gonadotropins stimulate the activation of cAMP-dependent-protein kinase that activates this enzyme by phosphorylating specific serine residues, thus promoting binding of the sterol esterase to lipid droplets and the hydrolysis of cholesterol esters.

Cholesterol is converted into pregnenolone, and the rate of pregnenolone synthesis is determined by:


4 Steroids – Basic Science

dihydrotestosterone), glucocorticoid (cortisol, corticosterone), and mineralocorticoids





Cells synthesizing steroid hormones (steroidogenic cells) use several pathways that ensure

2. The mobilization of cholesterol esters stored in lipid droplets through cholesterol-ester

3. The uptake of blood lipoproteins carrying cholesterol (low-density (LDL) and high-

The incorporation of lipoproteins into the cells is mediated by a receptor-endocytic mechanism that delivers the lipoproteins to the lysosomes where apolipoproteins are degraded. High density lipoproteins (HDL) are incorporated by the scavenger receptor class B, type I (SR-BI)-mediated selective uptake. Depending on the cell, the synthesis of lipoprotein receptors is stimulated by the adreno-corticotropin-hormone (ACTH) and luteinizing hormone (LH). The source of cholesterol for steroidogenesis varies according to the animal studied (Azhar et al., 2003; Hu et al., 2011). SR-BI synthesis in adrenal cells is

The membrane-bound transcription factor sterol regulatory element binding protein (SREBP) is the main regulator for cholesterol synthesis and cellular uptake. In mammalian cells, protein Insig, an endoplasmic- reticulum membrane protein, controls the activity of SREBP and the sterol-dependent degradation of the biosynthetic enzyme HMG-CoA

The cholesterol side chain cleavage reaction is the first step, and also the rate-limiting process in steroid hormone synthesis. The reaction takes place on the inner mitochondrial membranes and is catalyzed by the cholesterol-side-chain cleavage enzyme, cytochrome P-450scc; Cyp11a1 (Straus & Hsue, 2000). The translocator protein (TSPO) and the steroidogenic acute regulatory (StAR) protein mediate this transfer. TSPO is a high-affinity cholesterol-binding mitochondrial protein and StAR is a hormone-induced mitochondria protein that initiates the transfer of cholesterol into the mitochondria (Hu et al., 2010). In

the constant supply of cholesterol for steroid hormone synthesis, including:

stimulated by ACTH and inhibited by glucocorticoids (Mavridou et al., 2010).

1. De novo synthesis from acetate in the endoplasmic reticulum;


All steroid hormones derive from cholesterol in a process that includes:


and elimination of catabolites by urine, bilis or feces;


(aldosterone, deoxicorticosterone).

the blood stream;

urine, bilis or feces.

hydrolase;

density lipoproteins (HDL).

reductase (Espenshade & Hughes 2007).

steroid hormones as precursors;

**3. Capture and processing of cholesterol** 

Acute alterations in steroidogenesis generally result from changes in the delivery of cholesterol to P-450scc, whereas long-term alterations involve changes in the quantity of enzyme proteins, as well as cholesterol delivery (Straus & Hsue, 2000).
