These two hormones are released by the female and male reproductive organs, respectively. Other steroid hormones include aldosterone and cortisol, which are released by the adrenal glands along with some other types of androgens.
Steroid hormones are insoluble in water, and they are transported by transport proteins in blood. As a result, they remain in circulation longer than peptide hormones.
For example, cortisol has a half-life of 60 to 90 minutes, while epinephrine, an amino acid derived-hormone, has a half-life of approximately one minute.
Figure 1. Gold-labeled secondary antibodies against V5 or cMyc antibody localized SR-BI to these sites, and revealed substantial dimer formation of this protein--shown by close contact between gold particles [ , ]. From the above discussion it is apparent that while the understanding of the functional significance of SR-BI dimerization in steroidogenic tissues and cell lines which utilize the selective pathway for cholesterol transport is improving, the structural basis of the intramolecular interactions involved in SR-BI dimerization and function is not completely understood.
In an effort to further expand our understanding about the structure-function relationships and dynamics of SR-BI activity, we recently carried out studies aimed at determining the structural and functional contributions of cysteine residues within the SR-BI.
With the exception of C21, the remaining seven residues are highly conserved in other species including the mouse, hamster, rabbit, pig, cow, dog, tree shrew and human. The remaining three cysteine residues are equally distributed in the N-terminal transmembrane domain C21 , N-terminal half of the ECD C , and the C-terminal domain C Given that the extracellular domain contains six conserved cysteine residues, these could form up to three disulfide bonds, which in turn could help to stabilize the confirmation of SR-BI or participate in its dimerization.
Interestingly, mutation of any of these four cysteine residues to serine resulted in a robust induction of SR-BI dimer formation, but they are rendered non-functional because these residues are most likely also essential for the optimal HDL binding and hence, the selective CE uptake. Although selective uptake of cholesteryl esters for all practical purposes is considered to be non-endocytic, at least from the point of view of uptake of the intact lipoprotein particle, there are controversies regarding cholestryl ester movement to lipid droplets.
However, there are some suggestions that HDL-cholesteryl esters are delivered to the cell interior by the retero-endocytosis, where the receptor-bound HDL particle analogous to the transferrin receptor system is internalized, traverses an intracellular pathway during which cholesteryl esters are transferred to the cell interior and the HDL particle is recycled back to the plasma membrane where the lipid depleted HDL is now released [ — ].
This possibility appears to be weak given the overwhelming morphological evidence both at the light- and electron microscopic evidence showing that in vivo and in vitro HDL-cholesteryl ester delivery to adrenal and ovarian luteal tissues and cultured cells, respectively, does not involve internalization of the intact HDL particle itself, [ 73 , 90 , , , , , ]. It is possible that a small amount of HDL internalization in cultured cells reported by some investigators was in fact due to non-specific endocytosis of the HDL particle; indeed, there is considerable in vitro evidence that cultured cells can internalize a variety of receptor ligands in a non-specific manner [ — ].
It has also been suggested that HDL- cholesteryl esters are delivered to intracellular membranes via the formation of complexes with caveolin, annexin and cyclophilins [ ]. In this regard, it is noteworthy that caveolin is a component of several intracellular vesicle populations, caveolin-1 is required for lipid droplets formation, and all forms of caveolins i. 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 ].
Existing literature also supports this possibility given that fatty acid composition of cholesteryl esters in the rodent adrenal and ovary is significantly different from that of plasma or HDL, i. A combination of vesicular and non-vesicular transport processes most likely facilitates the transport of the newly released free cholesterol to the ER for its esterification and subsequent storage in lipid droplets [ 55 , 57 , 66 , ]. Steroid producing cells through the use of multiple cholesterol supply sources discussed above maintain adequate cholesterol reserves primarily in the form of lipid droplets that enable them to quickly respond to tropic hormone stimulation with the rapid mobilization of cellular cholesterol reserves and ensuing transport to mitochondria for steroidogenesis.
In adrenal and ovarian cells, cellular stores of cholesterol esters are constantly replenished by the delivery of plasma cholesterol through endocytic or selective pathway depending on species and lipoprotein type , whereas this chore in Leydig cells, under normal physiological conditions, is mainly achieved through increased de novo cholesterol synthesis.
During acute hormonal stimulation, these endogenously stored cholesterol esters are rapidly mobilized hydrolyzed and released free-cholesterol is efficiently transported to and within the mitochondria for its conversion to pregnenolone, the precursor of all steroid hormones.
This entire process involving the intracellular cholesterol mobilization, processing and transport to the appropriate site within the mitochondria for side-chain cleavage and pregnenolone production can be broadly divided into two separate, but equally important segments: a mobilization of cholesterol from intracellular stores, particularly from lipid droplets; b transport of mobilized cholesterol to the outer mitochondrial membrane; and c , transfer of this cholesterol from the outer to the inner mitochondrial membrane.
In the following sections, we will discuss characteristics of these three segments of intracellular cholesterol transport and also summarize current understanding about the functional roles of key proteins and factors involved in the mobilization of cellular cholesteryl esters, intracellular transport of newly released cholesterol to the outer mitochondrial membrane and its subsequent translocation to the inner mitochondrial membrane for the initiation of steroidogenesis.
This mobilization of substrate cholesterol occurs through tropic hormone-mediated increased formation of second messenger, cAMP followed by activation of PKA, and PKA-mediated phosphorylation activation of neutral cholesteryl ester hydrolase nCEH , resulting in rapid hydrolysis of cholesteryl esters [ 21 — 24 , 24 , 78 — 80 , — ].
We reported that hormone-sensitive lipase HSL is responsible for the vast majority, if not all, of nCEH activity in the adrenal [ ]. Current evidence also suggests that HSL is likely to function as a cholesteryl ester hydrolase in the ovary [ — ].
There is also a testis-specific isoform of HSL with a molecular mass of kDa [ 80 — 82 ]. This kDa isoform is predominantly expressed in germ cells of the testis and its expression is hormonally regulated [ ]. However, the identity and expression of HSL in testosterone producing testicular Leydig cells has yet to be established. The newly released cholesterol is transported to the outer mitochondrial membrane OMM for the production of steroid hormones.
Because cholesterol is a hydrophobic molecule and diffuses poorly in an aqueous environment, it can traverse from the cytoplasmic locations to the OMM by several potential mechanisms [ 54 — 57 , 66 ].
Cholesterol can be transported via the vesicular transport mechanism, i. However, this pathway appears to play a minor role [ 55 , 84 ]. Cholesterol may also be delivered to OMM via protein-protein interactions between the lipid droplets and mitochondria. As early as in , electron microscopic observations provided evidence suggesting that lipid droplets become juxtaposed during stimulation by tropic hormone [ ].
In the last few years, additional evidence has emerged showing potential interactions between lipid droplets and cellular organelles including mitochondria in several cell systems [ 69 , — ]. SNARE complexes facilitate fusion between transport vesicles and target membranes during protein trafficking [ — ]. More recently, another report provided direct evidence showing that the SNAP23 protein promotes interaction between lipid droplets and mitochondria [ ].
These various observations strongly suggest that SNARE proteins may mediate the transport of cholesterol substrate from lipid droplets to steroidogenic mitochondria, most likely by promoting the functional interaction between lipid droplets and mitochondria. A second potential mechanism by which mobilized cholesterol from lipid droplets may be delivered to the mitochondrial for steroid synthesis is through a non-vesicular transport process involving high-affinity cholesterol binding proteins [ 55 , 57 , 66 , 84 , ].
Earlier studies indicated that sterol carrier protein 2 SCP 2 , a nonspecific lipid transfer protein, mediates cholesterol transport to steroidogenic mitochondria and also stimulates steroid hormone biosynthesis [ — ]. Contrary to these findings, more recent metabolic and genetic evidence suggests that SCP 2 mainly functions as a carrier for fatty acyl CoAs, facilitates branched-chain fatty acid oxidation and regulates the distribution of key lipid signaling molecules e.
StarD4 and StarD5 are widely expressed in steroid producing cells, while StarD6 expression appears to be mostly restricted to the testicular germ cells [ , ]. Both StarD4 and StarD5, however, bind free cholesterol with high-affinity and specificity, facilitate cholesterol transport through an aqueous environment and have been shown to play important roles in the maintenance of cellular cholesterol homeostasis [ , ].
The ability and specificity of StarD4 and StarD5 to bind cholesterol, coupled with their high levels of expression in steroidogenic tissues, raises the strong possibility that StarD4 and StarD5 facilitate cholesterol transport to the outer mitochondrial membrane.
However, confirmation of this possibility must await the relevant experimental evidence. Extensive but mostly circumstantial evidence suggests that cellular architecture and cytoskeletal elements, in particular, vimentin-intermediate filaments IF, Type III may also be involved in facilitating cholesterol transport to mitochondria [ 8 , , ].
Vimentin-intermediate filament constitutes part of the network of the cytoskeleton [ ]. It is expressed in many cell types including adrenal, ovarian and testicular Leydig cells [ — ].
Several different reports of proteomic analyses of lipid droplets isolated from cells have consistently identified vimentin as a lipid droplet associated protein [ — ].
Vimentin has been shown to interact with several different proteins, including some motor-like propertiesand sterol binding properties [ — ]. The overexpression of ORP4, which interacts with vimentin and causes its aggregation, results in a defect in cholesterol esterification [ ]. Likewise, adrenal cells lacking vimentin display a defect in the re-esterification of LDL cholesterol without any alterations in LDL-receptor-mediated endocytosis [ ]. Hall and colleagues reported a close association of both functional mitochondria and cholesterol-enriched lipid droplets with the intermediate filaments in Y1 adrenal tumor cells, and testicular Leydig cells and suggested the possibility that such binding may facilitate the transport of cholesterol to mitochondria for steroid synthesis [ — ].
Furthermore, binding of lipid droplets and mitochondria to vimentin-intermediate filaments may also provide an ideal platform for docking of lipid droplets to the mitochondria and secondarily increased cholesterol transport to mitochondria.
Besides morphological evidence, a number of biochemical studies employing pharmacological inhibitors raised the possibility that cytoskeletal elements including vimentin may contribute to the cholesterol transport to mitochondria and the regulation of steroidogenesis although conflicting results have been generated [ ].
Also, it is important to realize that agents which were previously used in many of these studies to disrupt microfilaments, e.
The second critical step in steroid hormone biosynthesis is delivery of the cholesterol substrate to the inner mitochondrial membrane IMM sites, where cholesterol side-chain cleavage Pscc is located, and the enzyme that catalyzes the conversion of cholesterol to pregnenolone takes place [ 3 — 6 , 8 ]. This step is rate-limiting because the hydrophobic cholesterol cannot freely diffuse through the aqueous intermembrane space of the mitochondria to support acute steroid synthesis and requires the participation of a de novo synthesized labile protein [ 8 , 47 — 50 , — ].
This putative labile protein evaded detection for almost twenty years until when Orme-Johnson's laboratory first demonstrated that acute ACTH stimulation of adrenocortical cell steroidogenesis was accompanied by a rapid induction of 37 kDa phosphoprotein [ ]. Subsequent studies from her laboratory provided further characterization of this phosphoprotein in the adrenal and also demonstrated its presence and hormonal induction in corpus luteum and testicular Leydig cells [ — ].
Stocco and colleagues confirmed these observations in MA Leydig tumor cells, and subsequently cloned this protein and named it steroidogenic acute regulatory protein StAR [ , ]. StAR has been cloned from many species and is highly conserved across the species [ ]. StAR protein possesses all of the necessary characteristics of the acute regulator of steroid synthesis in steroidogenic cells i.
The role of StAR protein in the regulation of acute hormonal steroidogenesis was supported by three lines of evidence. First, transfection of a model testicular Leydig cell line MA cells with a StAR plasmid stimulated steroid production to the same extent as that seen with a maximum stimulating dose of cAMP analog [ ]. Second, co-transfection of StAR plus a fusion protein complex of Pscc plasmids in a heterologous cell system produced several-fold more pregnenolone steroid as compared to cells transfected with Pscc fusion complex alone [ , ].
Third, the most compelling evidence for a role of StAR in steroiodogenesis was provided by demonstrating that mutations in the StAR gene cause a fatal condition in newborns, the congenital lipoid adrenal hyperplasia lipoid CAH , characterized by severe impairment of steroiodogenesis, hypertrophied adrenals containing high levels of cholesterol esters and free cholesterol and increased amounts of neutral lipids in the testicular Leydig cells [ , ].
Depletion of the murine StAR gene by homologous recombination yielded an identical phenotype of impaired steroidogenesis and lipid accumulation in the adrenal and gonads [ , ].
In accordance with its role in the acute regulation of steroidogenesis, StAR is expressed mainly in the adrenal cortex, steroid producing cells of the ovary and testicular Leydig cells [ , ]. Significant expression of StAR is also reported in the rodent brain cell type that parallels the expression of Pscc and other steroidogenic enzymes, but its potential role in neurosteroidogenesis is not yet established [ 84 ].
In contrast, StAR expression is not detected in another major steroidogenic tissue, the placenta, which secretes progesterone constitutively [ , ]. StAR is synthesized as a short-lived cytoplasmic kDa protein with a mitochondrial targeting peptide that is cleaved upon mitochondrial import to yield the long-lived intramitochondrial kDa form [ 84 , , ].
StAR functions as a sterol transfer protein, binds cholesterol, mediates the acute steroidogenic response by moving cholesterol OMM to IMM, acts on the OMM, and requires structural change previously described as a pH-dependent molten globule [ — ]. Given that StAR StarD1 acts on the outer membrane in mediating the transfer of cholesterol from the OMM to the IMM, and raises the possibility that it may be a component of a multi-protein complex [ 84 , — ].
Several lines of evidence indicate that peripheral-type benzodiazepine receptor PBR is also involved in mitochondrial import of cholesterol substrate [ , ]. PBR, which is now referred to as translocator protein 18 kDa, TSPO is a high-affinity drug- and cholesterol-binding mitochondrial protein, with a cytoplasmic domain containing a cholesterol recognition amino acid consensus CRAC domain [ ].
TSPO is expressed ubiquitously in the OMM, but is more abundant in the adrenal gland and steroidogenic cells of gonads [ , , — ]. TSPO ligands stimulate steroid synthesis and promote translocation of cholesterol from OMM to the IMM in testicular Leydig cells, ovarian granulosa cells, and adrenocortical cells [ , , — ].
Targeted deletion of the TSPO gene in a Leydig cell line TSPO-deficient R2C cells blocked cholesterol transport into the mitochondria and dramatically reduced steroid production, whereas reintroduction of TSPO in the deficient cell line restored the steroidogenic capacity [ ].
Increasing evidence now suggests that TSPO and StAR interact functionally in mediating the transfer of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane. However, using a complementary bioluminescence resonance energy transfer, the same laboratory was unable to provide evidence for protein-protein interaction between TSPO and StAR [ ]. Interestingly, re-introduction of recombinant TSPO into the mitochondrial environment in vitro restored the steroidogenesis [ ].
Steroid producing cells have a dual requirement for cholesterol: they need cholesterol for membrane biogenesis and cell signaling as well as starting material for the mitochondrial synthesis of pregnenolone, the precursor steroid required for the formation of glucocorticoids, mineralocorticoids, and sex-steroids.
For steroid hormone production to proceed normally, adequate cholesterol must be available and supplied to the mitochondria. Under most physiological conditions, the supply of cholesterol is not rate-limiting, because there are multiple pathways that can fulfill the cholesterol needs of the cell. Although cellular de novo cholesterol synthesis and cholesteryl esters stored in lipid droplets can potentially supply adequate amounts of cholesterol substrate to support steroidogenesis, adrenal and ovary and testicular Leydig cells under certain conditions , they however, preferentially utilize plasma lipoprotein-derived cholesterol for steroid synthesis.
Its functional efficiency, however, is dictated by the physiological status of the steroidogenic cell, the species and the type and composition of circulating lipoproteins. Steroidogenic cells can also process exceptionally large quantities of lipoprotein-derived cholesteryl esters through the "selective" cholesteryl ester uptake pathway. Indeed, the "selective" cholesterol uptake pathway is quantitatively the most important source for cholesterol delivery for steroidogenesis in the tropic-hormone stimulated rodent adrenal and ovary.
The "selective" cholesterol uptake pathway involves internalization of cholesteryl esters from cell surface bound cholesterol-rich lipoproteins HDL or LDL, regardless of lipoprotein composition without the parallel uptake and lysosomal degradation of the lipoprotein particle itself. Hormone regulatable scavenger receptor class B, type I SR-BI is a physiologically relevant cell surface receptor responsible for "selective" uptake of lipoprotein-derived cholesteryl esters.
The mechanisms by which plasma-lipoprotein cholesterol is delivered to steroidogenic cells via the SR-BI mediated "selective" uptake pathway has been extensively studied, but remains incompletely understood.
Based on the current evidence, it appears that selective transfer of cholesterol esters to plasma membrane and their subsequent delivery to the cell interior by SR-BI requires the participation of accessory proteins, alterations in physicochemical characteristics of the plasma membrane e. The second step in cholesterol utilization for steroid hormone synthesis is intracellular cholesterol mobilization and processing and transport to the appropriate site within the mitochondria for side-chain cleavage and pregnenolone production.
This process can be broadly divided into three separate, but equally important segments: a tropic hormone-induced mobilization of cholesterol from intracellular stores, particularly from lipid droplets, transport of newly released free cholesterol to the outer mitochondrial membrane; and b transfer of this cholesterol from the outer to the inner mitochondrial membrane for steroid pregnenolone production.
Tropic hormone-mediated increased formation of the second messenger, cAMP, stimulates cAMP-PKA resulting in activation of cholesteryl ester hydrolase, and rapid hydrolysis of cholesteryl esters. The newly released cholesterol is transported to the outer mitochondrial membrane, although the actual underlying mechanism is not defined. Based on the currently available information, it appears that transport of hydrophobic cholesterol from the aqueous environment to OMM is primarily facilitated by the non-vesicular cholesterol transport mechanism involving StarD proteins such as the StarD4 and StarD5 family, which avidly bind cholesterol.
The next step in cholesterol transport to mitochondria is the transfer from the outer to the inner mitochondrial membrane; this is considered as a rate-limiting step in hormone-induced steroid formation. Two proteins, translocator protein 18 kDa, TSPO and steroidogenic acute regulatory StAR protein, which presumably work in concert, mediate this transfer. TSPO, previously known as the peripheral-type benzodiazepine receptor, is a high-affinity drug- and cholesterol-binding mitochondrial protein.
Communication between neighboring cells, and between cells and tissues in distant parts of the body, occurs through the release of chemicals called hormones. Hormones are released into body fluids usually blood that carry these chemicals to their target cells.
At the target cells, which are cells that have a receptor for a signal or ligand from a signal cell, the hormones elicit a response. The cells, tissues, and organs that secrete hormones make up the endocrine system.
Examples of glands of the endocrine system include the adrenal glands, which produce hormones such as epinephrine and norepinephrine that regulate responses to stress, and the thyroid gland, which produces thyroid hormones that regulate metabolic rates.
Although there are many different hormones in the human body, they can be divided into three classes based on their chemical structure: lipid-derived, amino acid-derived, and peptide peptide and proteins hormones. One of the key distinguishing features of lipid-derived hormones is that they can diffuse across plasma membranes whereas the amino acid-derived and peptide hormones cannot.
Most lipid hormones are derived from cholesterol and thus are structurally similar to it, as illustrated in Figure The primary class of lipid hormones in humans is the steroid hormones. Examples of steroid hormones include estradiol, which is an estrogen , or female sex hormone, and testosterone, which is an androgen, or male sex hormone.
These two hormones are released by the female and male reproductive organs, respectively. Other steroid hormones include aldosterone and cortisol, which are released by the adrenal glands along with some other types of androgens. Steroid hormones are insoluble in water, and they are transported by transport proteins in blood. As a result, they remain in circulation longer than peptide hormones.
For example, cortisol has a half-life of 60 to 90 minutes, while epinephrine, an amino acid derived-hormone, has a half-life of approximately one minute. The amino acid-derived hormones are relatively small molecules that are derived from the amino acids tyrosine and tryptophan, shown in Figure These hormones cannot pass through plasma membranes of cells; therefore, their receptors are found on the surface of the target cells.
Privacy Policy. Skip to main content. The Endocrine System. Search for:. Types of Hormones. Hormone Functions The endocrine system plays a role in growth, metabolism, and other processes by releasing hormones into the blood. Learning Objectives Evaluate hormones and their purpose in the body. Key Takeaways Key Points Hormones serve as chemical messengers in the body and help maintain homeostasis.
Hormones are released into bodily fluids, like blood, which carry them to target cells. Target cells respond to a hormone when they express a specific receptor for that hormone.
Hormones also play a role in the regulation of cell death, the immune system, reproductive development, mood swings, and hunger cravings. In the adrenal gland, epinephrine and norepinephrine regulate responses to stress; in the thyroid gland, thyroid hormones regulates metabolic rates. Key Terms target cell : any cell having a specific receptor for a hormone hormone : any substance produced by one tissue and conveyed by the bloodstream to another to affect physiological activity endocrine system : a control system of ductless glands that secrete hormones which circulate via the bloodstream to affect cells within specific organs.
Lipid-Derived, Amino Acid-Derived, and Peptide Hormones All hormones in the human body can be divided into lipid-derived, amino acid-derived, and peptide hormones.
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