19: Cholesterol II

Question 1

______ is the precursor of all steroid hormone classes (glucocorticoids, mineralocorticoids and the sex hormones (androgens, estrogens and progestins).

Answer 1

Cholesterol is the precursor of all steroid hormone classes (glucocorticoids, mineralocorticoids and the sex hormones (androgens, estrogens and progestins).

Question 2

Cholesterol synthesis uses primarily _____ mixed function oxidases (CYP) and occurs in the adrenal cortex (cortisol, aldosterone, androgens), ovaries and placenta (estrogens and progestins), and the testes (testosterone).

Answer 2

Cholesterol synthesis uses primarily Cytochrome P450 mixed function oxidases (CYP) and occurs in the adrenal cortex (cortisol, aldosterone, androgens), ovaries and placenta (estrogens and progestins), and the testes (testosterone).

Question 3

The first step, conversion of cholesterol to ______ by the _______ P450SCC is the rate limiting step.

Answer 3

The first step, conversion of cholesterol to pregnenolone by the side chain cleavage enzyme P450SCC is the rate limiting step.

This rxn occurs in the inner mitochondrial membrane. The rxn requires NADPH & O2.

Cholesterol within the cell moves to the mitochondrial outer membrane and then moves to the inner mitochondrial membrane. This latter step is mediated by STAR (steroidogenic acute regulatory protein).

Pregnenolone is the the precursor of all steroid hormones. It is oxidized and isomerized to Progesterone which is further modified by hydroxylation reactions occurring in the mitochondria and ER. The enzymes are primarily cytochrome P450 (CYP) proteins.

A defect at any step in these pathways can cause several diminished products at later steps and at the same time a build up of substrates at prior steps. Serious metabolic imbalance occurs with these enzyme deficiencies which cause disorders known as congenital adrenal hyperplasias.

Question 4

Deficiencies in enzymes involved in synthesis of the steroid hormones causes build up of prior substrates and diminishment of products. This causes a class of diseases called _______.

Answer 4

Deficiencies in enzymes involved in synthesis of the steroid hormones causes build up of prior substrates and diminishment of products. This causes a class of diseases called congenital adrenal hyperplasias.

Question 5

At the cellular level steroid hormones enter cells through the plasma membrane, the complex enters the nucleus and _______. The resulting ligand-receptor complex binds either co- activators or co-repressors and this complex binds _______ which either increase or decrease transcription.

Answer 5

At the cellular level steroid hormones enter cells through the plasma membrane, the complex enters the nucleus and dimerizes. The resulting ligand-receptor complex binds either co- activators or co-repressors and this complex binds HRE Dana elements which either increase or decrease transcription.

Steroid hormones travel in the blood from their point of synthesis vis specific & nonspecific (albumin) carrier proteins. Steroid hormones enter cells via the plasma membrane & once inside bind a receptor in the cytoplasm or nucleus. The receptor can bind both the steroid hormone and specific DNA hormone response elements, once homo-dimerized, resulting in altered transcription.

Question 6

The D Vitamins are a group of _____ that function like hormones.

Answer 6

The D Vitamins are a group of sterols that function like hormones.

Question 7

The active molecule: ________ binds
to receptor proteins within the cell. The ligand receptor complex interacts with DNA in a manner similar to the steroid hormones and enhances or represses transcription of a coordinated set of genes.

Answer 7

The active molecule: 1,25-dihydroxycholecalciferol (aka 1,25-diOH-D3 or calcitriol) binds
to receptor proteins within the cell. The ligand receptor complex interacts with DNA in a manner similar to the steroid hormones and enhances or represses transcription of a coordinated set of genes.

Question 8

The most important functions of 1,25-diOH-D3 (1,25-dihydroxycholecalciferol or calcitrol) is to regulate plasma levels of _____ and _______.

Answer 8

The most important functions of 1,25-diOH-D3 is to regulate plasma levels of calcium and phosphorous.

Question 9

Vitamin D defieciency can lead to _______ in children and __________ in adults due to incomplete mineralization of developing bone (Rickets) or bone demineralization (Osteomalacia).

Answer 9

Vitamin D defieciency can lead to Ricketts in children and Osteomalacia in adults due to incomplete mineralization of developing bone (Rickets) or bone demineralization (Osteomalacia).

Question 10

Name a Glucocorticoid:

Name a Mineralocorticoid:

Name Sex Hormones:

What does the adrenal cortex secrete?

What do the ovaries & placenta secrete?

What do the testes secrete?

Answer 10

Name a Glucocorticoid: cortisol

Name a Mineralocorticoid: aldosterone

Name Sex Hormones: androgens, estrogens, progestins

What does the adrenal cortex secrete? cortisol, aldosterone, and androgens

What do the ovaries & placenta secrete? estrogens and progestins

What do the testes secrete? testosterone

Question 11

Discuss cortisol

Answer 11

Cortisol is produced in the middle layer of the adrenal cortex called the zona fasiculata. In response to stress like an infection, corticotropin releasing hormone (CRH) made in the hypothalamus, travels through the capillaries to the anterior pituitary. @ the anterior pituitary, CRH induces the production/ secretion of adrenocorticotropic hormone ACTH. ACTH causes the adrenal cortex to synthesize & secrete the glucocorticoid cortisol. Cortisol helps the body respond to stress by stimulating gluconeogenisis & the inflammatory & immune response.

Question 12

List the steps of cortisol synthesis

Answer 12

ACTH binds to a G protein coupled receptor which increases cAMP which increases PKA. PKA phosphorylates & activates the lipase which converts cholesterol ester to cholesterol & STAR protein which allows the cholesterol to move in the inner mitochondrial membrane where it is converted to pregnenolone.

Pregenolone is then returned to the cytosol where it is converted to progesterone.

In 2 ER membrane hydroxylation steps catalyzed by CYP 17 & CYP 21, progesterone is converted to 11 deoxycortisol. After this, 11-deoxycortisol is returned to the inner mitochondrial membrane where CYP11B1 catalyzes the B-hydroxylation @ c21 yeilding cortisol which can enter the cell..

Question 13

Discuss aldosterone

Answer 13

Aldosterone is produced in the outer layer of the adrenal cortex called zona glomerulosa. Its production is stimulated by a decrease in plasma Na+/K+ ratio and by angiotensin II. Angiotensin II is produced by cleavage of the decapeptide angiotensin I by Angiotensin converstin enzyme ACE. Angiotensin I is made in the blood by cleavage of angiotensinogen & renin.

Aldosterone’s effect is on the kidney tubules where it enhances Na+ & water uptake & K+ efflux (Water follows sodium uptake).

Aldosterone increases blood pressure & ACE inhibitors are used to treat renin dependent hypertension.

Question 14

Discuss sex hormones

Answer 14

Androgens or sex hormones are produced by the inner (reticularis) & middle (fasiculata) zones of the adrenal cortex. Adrenal androgens are converted to testosterone & estrogen in peripheral tissues.

Hypothalamic releasing factor Gonadotropin-releasing hormone, GRH, stimulates the anterior pituitary to release lutenizing hormone LH & follicule stimulating hormone FSH–both are glycoproteins. FSH & LH bind to G protein receptors & increase cAMP & PKA.

Estrogens are produced from androstenedione & then testosterone by aromatase. Aromatase inhibitors are used for estrogen responsive breast cancer in post-menopausal women.

Question 15

LH stimulates the testes to produce ______. FSH stimulates ______ within the testes.

LH stimulates the ovaries to produce ______ & ______. FSH regulates the growth of ______ ______.

Answer 15

LH stimulates the testes to produce testosterone. FSH stimulates spermatogenesis within the testes.

LH stimulates the ovaries to produce estrogens & progesterone. FSH regulates the growth of ovarian follicles.

Question 16

Describe steroid hormone action @ the molecular level.

Answer 16

Steroid hormones are sufficiently hydrophobic to diffuse through the plasma membrane of cells.

Inside the cells they bind a cytoplasmic or nuclear receptor. If not already in the nucleus, then the ligand-receptor complex enters the nucleus & dimerizes & binds a regulatory sequence called the hormone response element-HRE.

HRE is found in the promoter or an enhancer element. In the presence of a coactivator protein mRNA transcription is increased. Note that these ligand-receptor complexes may also decrease transcription of genes when associated with co-repressors.

The binding of ligand to receptor causes a conformational change in the receptor which exposes a DNA binding domain. The complex may now associate with the DNA via a zinc-finger motif sequence in the receptor.

There is a superfamily of structurally related steroid receptors that bind steroids, thyroid hormone, retinoic acid (vitamin A), & vitamin D (1,25-hydroxycholecalciferol) which all function similarly.

Question 17

Discuss metabolism & excretion of steroid hormones.

Answer 17

Steroid hormones are converted to inactive excretion products in the liver. The rxns involve reduction of unsaturated double bonds & addition of hydroxyl groups.

Conjugation of steroids with glucaronic acid or sulfate makes the excretion products more water soluble (thus do not need protein carriers).

20-30% of these metabolites are secreted into the bile & excreted in the feces. the remainder are filtered in the kidneys before getting into urine.

Question 18

Discuss Vitamin D

Answer 18

Vitamin D (1,25-dihydroxycholecalciferol or calcitrol) = a group of sterols that behave like hormones. Vitamin D binds to receptor proteins inside the cell. The ligand-receptor complex interacts with DNA in a manner similar to steroids & enhances or represses transcription of genes.

The most important functions of vitamin D is to regulate plasma levels of calcium & phosphorus.

Vitamin D has endogenous & exogenous sources.

Endogenous: 7-dehydrocholesterol is converted to cholecalciferol in the dermis & epidermis when one is exposed to sunlight. Cholecalciferol is then transported to the liver bound to vitamin D-binding protein.

Exogenous (diet): Ergocalciferol (vitamin D2) is in plants & cholecalciferol (vitamin D3) is in animal tissues. Dietary vitamin D is packaged into chylomicrons. Vitamin D supplements are required for ppl with low exposure to sunlight.

D2 & D3 are not biologically active. They are converted in vivo to the active form of 1,25-diOH-D3 by two sequential hydroxylation rxns. The first rxn is in the liver & is done by 25 hydroxylase yeilding 25-hydroxycholecalciferol or calcidiol (storage form & plasma form of Vitamin D). Calcidiol is futher hydroxylated @ the 1 position by 25-hydroxycholecalciferol-1-hydrozylase in the kidney to make 1,25-diOH-D3. Both hydroxylases are cytochrome P450’s.

Question 19

How is 25-hydroxycholecalciferol-1-1hydroxylase regulated (rxn 2 in kidney):

Its activity is increased directly by low plasma ______

Its activity is increased indirectly by low plasma _____

Low calcium or hypocalcemia triggers secretion of parathyroid hormone _______.

Elevated levels of _______ inhibits activity of 25-hydroxycholecalciferol-1-1hydroxylase.

Answer 19

How is 25-hydroxycholecalciferol-1-1hydroxylase regulated (rxn 2 in kidney):

Its activity is increased directly by low plasma phosphate

Its activity is increased indirectly by low plasma calcium

Low calcium or hypocalcemia triggers secretion of parathyroid hormone PTH. PTH upregulates the enzyme (we are stealing the calcium from the bones to increase its concentration in the serum).

Elevated levels of 1,25-diOH-D3 inhibits activity of 25-hydroxycholecalciferol-1-1hydroxylase via negative feedback of product.

Question 20

Vitamin D stimulates calcium intestinal _______.

So low vitamin D = low calcium ______.

Answer 20

Vitamin D stimulates calcium intestinal absorption.

So low vitamin D = low calcium absorption.

Vitamin D binds to a ligand binding domain within the vitamin D receptor within the cytoplasm of the intestinal cell. Calbindin-D9K mediates the transport of calcium across the enterocytes from the apical side. Another calcium transport protein is TRPV5 which allows calcium into the epithelial cell. The transport of calcium across the enterocyte cytoplasm is rate limiting for calcium absorption in the intestine. The presence of Calbindin increases the amount of calcium crossing the cell without raising the free concentration.

Question 21

Hypocalcemia causes ______ of vitamin D & PTH. Both act to increase calcium ______ & bone ______ & inhibit calcium ______ out of the body.

______ plasma calcium blocks production of PTH & diminishes conversion of vitamin D. ______ levels of calcitonin result in inhibition of bone resorption & increase calcium excretion. High levels of plasma calcium & phosphate also ______ bone mineralization. When dietary vitamin D & calcium are adequate, no net loss of bone calcium occurs.

When vitamin D is deficient, there is ______ of bone due to increased PTH.

Answer 21

Hypocalcemia causes elevation of vitamin D & PTH. Both act to increase calcium absorption & bone resorption (demineralization) & inhibit calcium excretion out of the body.

High plasma calcium blocks production of PTH & diminishes conversion of vitamin D. Elevated levels of calcitonin result in inhibition of bone resorption & increase calcium excretion. High levels of plasma calcium & phosphate also increase bone mineralization. When dietary vitamin D & calcium are adequate, no net loss of bone calcium occurs.

When vitamin D is deficient, there is demineralization of bone due to increased PTH.

Question 22

What foods have Vitamin D?

25-OH-D3 is the major form of Vitamin D in ________ & is measured in clinical labs.

Answer 22

Vitamin D occurs in fatty fish, liver, & egg yolks. MILK IS NOT GOOD for vitamin D unless it is fortified with it.

25-OH-D3 is the major form of Vitamin D in serum & is measured in clinical labs.

Question 23

Vitamin D deficiency results in net _________ of bone resulting in rickets in _______ & osteomalcia in ______. Rickets is charictarized by formation of the collagen matrix but insufficient _________ resulting in soft bones. In osteomalacia, demineralization of existing bones makes them more succeptible to fracture. Bowing of legs occurs too.

Answer 23

Vitamin D deficiency results in net demineralization of bone resulting in rickets in children & osteomalcia in adults. Rickets is charictarized by formation of the collagen matrix but insufficient mineralizaiton resulting in soft bones. In osteomalacia, demineralization of existing bones makes them more succeptible to fracture. Bowing of legs occurs too.

Rickets is known as nutritional rickets.

Question 24

Renal osteodystrophy & hyperthyroidism have the same symptoms of _______ + _________.

Answer 24

hypocalcemia + hyperphosphatemia

Renal osteodystrophy = chromic kidney disease causes decreased synthesis of active vitamin D & increased retention of phospahte = hypocalcemia + hyperphosphatemia. Hypocalcemia increases PTH & bone demineraliztion. Treat by supplementing with calcitriol & reducing phosphate.

Hyperthyroidism = lack of PTH causes hypocalcemia + hyperphosphatemia. Treat with calcium + calcitrol.

Question 25

Describe vitamin D toxicity

Answer 25

Vitamin D is fat soluble (ADEK) & is stored in the body & is slowly metabolized. Those taking too much vitamin D supplements can lose appetite, have nausea, thirst, & stupor. There is enhanced calcium absorption & bone resporption which gives hypercalcemia which leads to calcium deposits in organs like the arteries & kidneys.