Cholesterol

Question 1

Where does cholesterol synthesis take place?

Answer 1

Liver

Question 2

What is cholesterol a precursor for?

Answer 2

Bile salts and steroid hormones

Question 3

How much cholesterol is synthesized de novo?

Answer 3

900 mg a day

Question 4

What does LDL derived cholesterol suppress?

Answer 4

Synthesis of cholesterol and LDL receptor

Question 5

What does insufficient cholesterol intake do?

Answer 5

Stimulate LDL reecptor synthesis

Question 6

What are the phases of cholesterol synthesis?

Answer 6

1) Acetyl CoA -> HMG CoA

2) Conversion of HMG-CoA to squaline
HMGR is the rate limiting enzyme in cholesterol synthesis

3)

Question 7

How does cholesterol degradation work?

Answer 7

Cholesterol cannot be degraded into smaller molecules?

Cholesterol is lost due to bile acid synthesis, hormone transformation, and excretion–these derivatives have a greater solubility which allows them to be secreted

Question 8

What is the most important cholesterol related mechanism?

Answer 8

Production of bile acids in the liver

Cholesterol -> 7-alpha-hydroxycholesterol
via cholesterol-7-hydroxylase (rate limiting enzyme)

Question 9

How does bile acid synthesis work?

Answer 9

One half of the cholesterol synthesized is used to produce bile acids

Occurs in liver

Cholic acid is one of the principal bile acids

7-alpha-hydroxylase is the rate limiting enzyme in bile acid synthesis

Cholic acid and deoxycholic acid

Question 10

What do bile salts do?

Answer 10

Help lipid digestion and fat soluble vitamins absorption in small intestine

Question 11

What is contained in bile?

Answer 11

Bile salts, cholesterol, phospholipids, bilirubin, biliverdin

Question 12

Where do bilirubin and biliverdin come from?

Answer 12

Degradation products of heme

Question 13

Most bile acids are conjugated with?

What effect does this have?

Answer 13

Glycine and taurine

Increases solubility

Question 14

How does cholesterol homeostasis occur?

Answer 14

Cholesterol homeostasis occurs through
intricate regulation through cholesterol
synthesis, LDL receptor activity, and bile
acid synthesis

Question 15

How does cholesterol biosynthesis regulation occur?

Answer 15

modulation of HMGR–enzyme and gene

HMGR–reducing HMG-CoA to coenzyme A–rate limiting step of sterol synthesis

HMGR activity is regulated by phosphorylation and
dephosphorylation

Question 16

What effects do hormones have on HMGR?

Answer 16

Glucagon and epinephrine depress HMGR activity by activating phosphoprotein phosphatase inhibitor (PPI) and increasing adenylate cyclase activity (which increase cAMP, and phosphorylates HMGR)

Insulin activates HMGR activity by inhibiting cAMP production, increase phosphodiesterase (which eats cAMP) and inhibits PPI

Question 17

Describe sterol mediated changes in gene expression that affect cholesterol homeostasis

Answer 17

The ER membrane protein Sterol-RegulatoryElement
Binding Protein-2 (SREBP2) is the
predominant regulator of cholesterol homeostasis

SREBP2 also regulates LDL receptor activity and NADPH synthesis

SREBP2 has a transcription factor domain on its N-terminus that is released when cholesterol levels are low

Question 18

How does SREBP regulate expression?

Answer 18

When cellular cholesterol is high,
cholesterol bound to SSD, the ER
retention protein Insig also bound

When cholesterol is depleted,
cholesterol no longer bound to
SSD
- Insig released
- SREBP/SCAP complex
transferred to Golgi complex

In Golgi, two proteases cleave at
two sites (see arrows) and releases
active TFD (transcription factor domain) from SRBP2

TFD moves into nucleus

TFD binds to sterol regulatory
elements (SER) that are
associated with sterol related
genes