Cholesterol and Steroid Synthesis

Question 1

HMG CoA Reductase

Answer 1

Rate Limiting enzyme in cholesterol synthesis

Converts HMG CoA to Mevalonate in cholesterol synthesis

Uses 2 NADPH

Inhibited by:
Cholesterol - feedback inhibitor

Glucagon - phosphorylates HMG CoA reductase via PKA pathway

Statin drugs - competitive inhibitor. (results in upregulation of the enzyme)

Increased AMP - activates AMP kinase that phosphorylates the enzyme.

Activated by:
Dephosphorylation by a phosphoprotein phosphatase (activated by insulin)

Question 2

Synthesis of HMG CoA

Answer 2

1) 2 Acetyl CoAs form Acetoacetyl CoA via thiolase

2) Acetoacetyl CoA combines with another Acetyl CoA to form HMG CoA via HMG CoA synthase

Question 3

SREBP

Answer 3

Sterol regulatory element binding protein

Binds to a region in the HMG CoA reductase gene called sterol responsive element (SRE) resulting in increased transcription/translation of the HMG CoA reductase

Question 4

Statin Treatment

Answer 4

Competitively inhibits HMG CoA Reductase
results in decreased liver cholesterol.

Decreased liver cholesterol signals an upregulation of LDL receptors on cell surface to increase intercellular cholesterol levels. results in decreased serum cholesterol.

Cholesterol from LDLs are sequestered as cholesterol esters via ACAT

Question 5

Smith-Lemli-Opitz Syndrome

Answer 5

A genetic defect of cholesterol synthesis
(autosomal recessive)

7-dehydrocholesterol reductase needed for the correct double bond formation in ring B, is partially deficient

is relatively common and leads to
microencephaly and other embryonic malformations.

Question 6

7-Alpha-hydroxylase

Answer 6

rate limiting enzyme in bile synthesis

Forms Cholic acid from Cholesterol

Question 7

Conjugated bile salts

Answer 7

Cholic Acid and Chenodeoxycholic Acid conjugated with glycine or taurine to form salts.

4 Functions of bile salts:

1. Only significant mechanism for the elimination of excess cholesterol.
2. Solubilize cholesterol in the bile
3. Facilitate the digestion of dietary TAGs by acting as emulsifying agents that render fats accessible to pancreatic lipases.
4. they facilitate the intestinal absorption of fat-soluble vitamins.

Question 8

Thiolase

Answer 8

Converts 2 Acetyl CoAs to Acetoacetyl CoA

Question 9

HMG CoA Synthase

Answer 9

Forms HMG CoA from Acetoacetyl CoA by the addition of a third Acetyl CoA

Question 10

5-Pyrophosphatemevalonate

Answer 10

Formed from Mevalonate and 2 ATP. Forms IPP and CO2. Requires ATP

Question 11

IPP

Answer 11

isopentenyl pyrophosphate (5C)

Formed from 5-Pyrophosphatemevalonate and ATP and giving off CO2.

Forms DPP via isomerization

Question 12

DPP

Answer 12

3,3-dimethylallyl pyrophosphate (5C)

Formed from IPP

Combines with another IPP to form GPP

Question 13

GPP

Answer 13

geranyl pyrophosphate (10C)

Formed from the combination of IPP and GPP

GPP reacts with another IPP to form FPP

Question 14

FPP

Answer 14

farnesyl pyrophosphate (15C)

Precursor of CoQ in the ETC

Two FPP combine in the presence of NADPH to form Squalene

Question 15

Squalene

Answer 15

Formed from the combination of two FPP

combines with O2 and NADPH to form Ianosterol

Question 16

Ianosterol

Answer 16

Precursor of Cholesterol

undergoes reduction, and removal of methyl groups to form cholesterol.

Question 17

5 classes of steroids

Answer 17

glucocorticoids, mineralocorticoids, androgens, estrogens and progestins

Question 18

Locations of cholesterol synthesis

Answer 18

Adrenal Cortex - Cortisol, aldosterone
Ovaries - estrogens and progestins
Testis - testosterone

Question 19

Pregnenolone

Answer 19

Important intermediate in steroid synthesis formed from cholesterol via desmolase.

Question 20

Desmolse

Answer 20

CYP 11A1, P450 scc

Converts Cholesterol to Pregnenolone. Requires O2 and NADPH

rate limiting step

Question 21

StAR

Answer 21

steroidogenic acute regulatory protein

Transports cholesterol into mitochondria for initial steps of steroid synthesis.

Question 22

Cotisol

Answer 22

Glucocorticoid synthesized from progesterone and released from zona fasciculata of the adrenal cortex.

stimulated by ACTH from the anterior pituitary.

increased gluconeogenesis
Anti-inflammatory action
Protein breakdown in muscle (counteracts insulin)

leads to inhibition of receptor- activated phospholipase A2

inhibits induction of COX-2

Involved in stress adaptation, and numerous effects on the immune system

Question 23

Aldosterone

Answer 23

mineralcorticoid, produced from progesterone in the zona glomerulosa of adrenal cortex

Stimulated by Angiotensin II/III

raises blood pressure and fluid volume, increases Na+ uptake

Question 24

Testosterone

Answer 24

Androgen from Zona reticularis of the adrenal cortex
Mainly dehydroepiandrosterone (DHEA) and androstenedione, but also some testosterone

Androgens are changed in fat cells to estradiol and in peripheral tissue (testes) to testosterone via aromatase

LH receptor in Leydig cells increases c-AMP and PKA resulting in testosterone synthesis

Stimulates spermatogenesis
Promotes male secondary sex characteristics

Question 25

Estrogens

Answer 25

From estradiol and produced in the zona reticularis.

stimulated by follicle stimulating hormone

control menstrual cycle
promote female secondary sex characteristics

Question 26

Addison’s disease

Answer 26

Adrenal cortex atrophy due to disease
● Mostly by autoimmune destruction
● Aldosterone and cortisol levels are low, and ACTH is high,

Failure to thrive, Muscle weakness, Fatigue, Weight loss, Hyperpigmentation, Salt craving, Hyponatremia, Hyperkalemia, Hypovolemia, Hypotension, Abdominal pain, Vomiting, Constipation

Question 27

Cushing’s Syndrome

Answer 27

Hypercortisolism

hyperfunction of the adrenal cortex, usually due to a tumor

High cortisol concentrations and low ACTH. Leads to protein loss and characteristic fat distribution in the face, and neck.

Hirsutism, early pubic hair development

Question 28

3-Beta Hydroxysteroid dehydrogenase

Answer 28

3-Beta

Converts pregnenolone to progesterone

Converts DHEA to Androstenedione
Converts 17-hydroxypregnenolone to 17-hydroxy progesterone

Deficiency results in virtually no corticosteroids, androgens or estrogens

Patients have famale-like genitalia and salt excretion in urine

Question 29

21-hydroxylase

Answer 29

21, or CYP21A2

Converts Progesterone to Deoxycorticosterone. precursor in the formation of aldosterone

Converts 17-hydroxyprogesterone to 11-deoxycortisol

Deficiency:
mineralcorticoids and glucocorticoids are virtually absent
Results in overproduction of androgens that leads to masculinization of external genitalia in females and virilization in males.

Question 30

17 Alpha Hydroxylase

Answer 30

CYP17 or 17 Alpha

Converts Progesterone to 17-alpha-hydroxyprogesterone

Converts 17-alpha-hydroxyprogesterone to Androstenedione

Deficiency:
no sex hormones or cortisol are produced
increased production of mineralcorticoids causes Na+ and fluid retention resulting in hpertension

Question 31

11 beta hydroxylase

Answer 31

11-beta or CYP11B1

Converts Deoxycorticosterone to corticosterone
Converts Deoxycorisol to cortosol

Deficiency:
Decrease in serum cortisol, aldosterone, corticosterone

Increased deoxycorticosterone causes fluid retention due to low renin (hypertension)

Overproduction of androgens

Question 32

Aldosterone Synthase

Answer 32

18, or CYP11B2

Converts cortiosterone to aldosterone

Question 33

Aromatase

Answer 33

CYP19

Converts Testosterone to Estradiol
Converts Androstenedione to Estrone

Question 34

Treatment of Cholelithiasis

Answer 34

chenodeoxycholic acid (Chenodiol)
Surgical removal of gall bladder
Disintegration of stones by shock waves
Dissolution with methyl-tert-butyl ether