Steroid hormones and nuclear receptors

Question 1

Which enzyme carries out steroid synthesis?

Answer 1

cytochrome p450 system: a a large superfamily of mixed function oxidases.

Question 2

What is the main job of the cytochrome p450 system?

Answer 2

xenobiotic detox system: oxidizes highly hydrophobic molecules that are otherwise toxic to the cell. This is done in the mito and ER.

Question 3

Where are cyt p450 system found?

Answer 3

mito and ER

Question 4

Describe the steps of metabolite (such as lipids and steroid hormones) oxidation by cyt p450.

Answer 4

1. CYP contains heme group with iron. Initially iron is oxidized as Fe3+. The CYP protein binds its hydrophobic substrate.
2. NADPH CYP reductase moves electrons from NADPH to iron, reducing it and making it ready to accept O2
3. The O2 oxidizes the substrate and creates H2O, and the oxidized substrate can leave CYP.

Question 5

What is another name for nuclear receptors?

Answer 5

txn factors

Question 6

How is cholesterol transported to the mito for oxidation by CYP?

Answer 6

Once in the cell, StAR transporter (gets across outer mito membrane) and translocator protein TPSO moves cholesterol across the membranes into the mito matrix.

Question 7

Which steroid hormone precursor does CYP make from cholesterol?

Answer 7

pregnenolone (serves as prohormone to make other steroid hormones)

Question 8

What are the major signals in steroid hormone synthesis, and what do they do?

Answer 8

1. corticotropin releasing hormone made in hypothalamus stimulates anterior pituitary to secrete ACTH
2. ACTH stimulate adrenal cortex to release steroid hormones, such as cortisol (steroid hormones can also be made in the sex glands).
3. cortisol negatively regulates hypothalamus and anterior pituitary.

Question 9

How does ACTH hormone stimulate synthesis of steroid hormones?

Answer 9

1. ACTH binds G protein coupled receptor, initiating phosphorylation cascade
2. cAMP activates PKA cascade, stimulating upregulation of StAR expression and increased cholesterol transport into the mitochondria.

Question 10

Describe aldosterone.

Answer 10

principal mineralcorticoid produced from progesterone. raises blood pressure and fluid volume, increases sodium uptake.

Question 11

describe testosterone

Answer 11

male sex hormone synthesized in testes, responsible for secondary male characteristics, produced from progesterone

Question 12

describe estradiol.

Answer 12

an estrogen, principle female sex hormone synthesized in the ovary, responsible for secondary female sex characteristics

Question 13

Describe cortisol.

Answer 13

dominant gluccocorticoid. synthesized from progesterone in adrenal cortex. involved in stress adaptation, metabolic energy signal, elevated blood pressure and sodium absorption, effects on immune system.

Question 14

Where on the chromosome do nuclear receptors bind?

Answer 14

hormone responsive elements. these are distributed across the chromosome.

Question 15

Describe the synthesis of pregnenolone from cholesterol.

Answer 15

The prohormone pregnenolone is made from the oxidation of cholesterol’s hydrophobic chain by cytochrome p-450SCC. Involves O2. Pregnenolone is therefore less hydrophbic than cholesterol. This takes place in the inner mito membrane

Question 16

How are estrogens made?

Answer 16

androgens are used as a template to make estrogens, using aromatase to turn the first ring into an aromatic ring. In breast cancer, aromatase is targeted to lower estrogen levels.

Question 17

What is cortisol binding globulin and what is its purpose?

Answer 17

It is a protein in the blood that allows cortisol to travel throughout the body. This is needed because cortisol is still relatively hydrophobic.

Question 18

PKA upregulates StAR expression. What other protein involved in cholesterol uptake does it upregulate?

Answer 18

lipoprotein lipases to free up cholesterol from lipid droplet

Question 19

Describe binding of steroid hormone to nuclear receptor.

Answer 19

The receptor is normally bound to heat shock protein in absence of ligand, keeping it inactive. Once the steroid hormone enters the cell and binds the receptor, HSP is shed and the receptor is activated and translocated to the nucleus via NLS. It then binds to hormone response element on the DNA and elicits a change in protein expression.

Question 20

How do general and specific txn factors differ?

Answer 20

GTFs are used throughout all of txn and activate promotors at a low, basal level. Specific transcription factors can up/down regulate the levels and rates of protein expression beyond the GTFs.

Question 21

Describe the structure of a nuclear receptor (specific transcription factor)

Answer 21

1. scaffold domain/activation domain for accessory proteins (these will allow the complex to interact with general txn factors)
2. DNA binding domain
3. hinge
4. ligand binding domain

Question 22

What are the nuclear receptor superfamilies?

Answer 22

1. type one: steroid ligands
2. type two: ligands are thyroid hormone, vitamin D, retinoic acid, lipid derivatives
3. type three: orphan receptors (ligands unknown)

Question 23

Which is the fight or flight steroid hormone?

Answer 23

cortisole

Question 24

How does cortisol carry out its function even during low energy?

Answer 24

-It stimulates gluconeogenic enzymes to generate energy for fight or flight. This is why it is called a gluocorticoid.

Question 25

What are the metabolic functions of cortisol?

Answer 25

• It can mobilize amino acids from muscle to use in gluconeogenesis.
• It inhibits uptake of glucose by muscle and adipose to conserve glucose
• it stimulates fat breakdown in adipose, providing energy (fatty acid oxidation) and glycerol (substrate for gluconeogenesis)

Question 26

What are the immune effects of cortisol?

Answer 26

• prevents release of inflammatory mediators
• downregulates IL2 receptors on helper T cells
• cortisol is used pharmaceutically to treat inflammation and allergies for these reasons

Question 27

How can cortisol have so many different effects on the cell?

Answer 27

Because each cell environment which receives cortisol is different.

• different transcriptional activators
• different mRNA profiles
• different splice sites for mRNA

Question 28

Which type of nuclear receptor does cortisol bind to?

Answer 28

Type one

Question 29

What tissue types are affected by cortisol?

Answer 29

• CNS
• lung
• cardiovascular
• adipose
• skeletal muscle
• liver
• bone
• immune cells

Question 30

What are some examples of type two nuclear receptors?

Answer 30

• thyroid hormone receptor
• non-steroidal lipids
• retinoic acid receptors
• vitamin D receptor
• peroxisome proliferator-activated receptors (PPAR)

Question 31

What vitamin is retinoic acid derived from?

Answer 31

vitamin A

Question 32

How do the type two nuclear receptors dimerize?

Answer 32

All of them dimerize with retinoid X receptor (RXR)

Question 33

What system are retinoic acid receptors involved in?

Answer 33

this type two nuclear receptor is necessary for growth and development. It can activate or repress gene expression depending on the local response element it binds to.

Question 34

How do the type two class PPAR receptors differ from one another?

Answer 34

They are given greek letters. These different PPAR receptors do different things even when expressed in the same tissues. They play a MAJOR role in metabolism.