Major pathway of steroid hormones biosynthesis

Bile acids, in particular chenodeoxycholic acid (CDCA) and cholic acid (CA), can regulate the expression of genes involved in their synthesis, thereby, creating a feed-back loop. The elucidation of this regulatory pathway came about as a consequence of the isolation of a class of receptors called the farnesoid X receptors, FXRs . The FXRs belong to the superfamily of nuclear receptors that includes the steroid/thyroid hormone receptor family as well as the liver X receptors (LXRs) , retinoid X receptors (RXRs), and the peroxisome proliferator-activated receptors (PPARs) .

The PPAR: RXR heterodimer exists in both an active and inactive state. When inactive, it is bound to corepressors such as the NCOR (Nuclear Receptor Corepressor) or the SMRT (Silencing Mediator For Retinoid and Thyroid Hormone Receptor). In the presence of ligand for either PPAR or RXR, the corepressors dissociate so that the ligand can bind and activate co-activators, such as SRC1 (Steroid Receptor Coactivator1), CBP/p300 (CREB-Binding Protein), the Tuberous Sclerosis Gene-2 product, the PPAR binding protein, P-GammaC1, P-GammaC2 (PPAR-Gamma Coactivator 1 and 2), and Ara70 (). The only known natural ligand for RXR is 9-cis Retinoic Acid. When the PPAR: RXR complex is activated, it binds to PPRE in the 5'region of target genes to induce transcription. PPAR-Alpha regulates the expression of genes involved in the peroxisomal and mitochondrial Beta-oxidation pathways such as Acyl-CoA oxidase, Enoyl-CoA hydratase/dehydrogenase multifunctional enzyme, Keto-Acyl-CoA thiolase, Malic enzyme, medium chain Acyl-CoA dehydrogenase, and mitochondrial hydroxy methylglutaryl-CoA synthase. PPAR-Alpha also regulates FATP (Fatty Acid Transport Protein), the FAT/CD36 (Fatty Acid Translocase), L-FABP (Liver Cytosolic Fatty Acid-Binding Protein) and UCP2 and UCP3 (Uncoupling Proteins-2 and 3). By altering transcription of these genes, activated PPAR-Alpha leads to increased breakdown of triglycerides and fatty acids, increased cellular fatty acid uptake, and reduced triglyceride and fatty acid synthesis. The expression of PPAR-Gamma is widespread and it is found at moderate levels in most tissues, with high levels of the protein found in the placenta and large intestine. The activity of PPAR-Alpha and PPAR-Gamma is also regulated by phosphorylation events. Specifically, the recruitment of adaptor molecules, including SHC (SH2 containing protein) and the GRB2 (Growth Factor Receptor-Bound Protein-2)-SOS complex by several growth factor receptors, which leads phosphorylation of Ras and Raf1 molecules. This in turn activates the MAPKs (Mitogen Activated Protein Kinases) of the ERK (Extracellular Signal Regulated Kinase) type, which occurs by sequential activation of TAK1 (TGF-Beta Activated Kinase-1) and MEKs (MAPK/ERK kinases). These kinases inhibit the activities of PPAR-Alpha and PPAR-Gamma. In contrast, GPCR (G-Protein Coupled Receptors) mediated phosphorylation of PKA (Protein Kinase-A) by cAMP (cyclic Adenosine-3, 5' Monophosphate) or p38 MAPK activates PPAR-Alpha. This differential regulation of PPAR activity by signal transduction events provides a mechanism for rapid, cell-specific control of PPAR target gene expression by extracellular stimuli ().

How might behaviors affect hormones? The birdsong example demonstrates how hormones can affect behavior, but as noted, the reciprocal relation also occurs; that is, behavior can affect hormone concentrations. For example, the sight of a territorial intruder may elevate blood testosterone concentrations in resident male birds and thereby stimulate singing or fighting behavior. Similarly, male mice or rhesus monkeys that lose a fight decrease circulating testosterone concentrations for several days or even weeks afterward. Comparable results have also been reported in humans. Testosterone concentrations are affected not only in humans involved in physical combat, but also in those involved in simulated battles. For example, testosterone concentrations were elevated in winners and reduced in losers of regional chess tournaments.

Major pathway of steroid hormones biosynthesis

major pathway of steroid hormones biosynthesis

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