Cholesterol Flashcards
Where does cholesterol synthesis take place?
Liver
What is cholesterol a precursor for?
Bile salts and steroid hormones
How much cholesterol is synthesized de novo?
900 mg a day
What does LDL derived cholesterol suppress?
Synthesis of cholesterol and LDL receptor
What does insufficient cholesterol intake do?
Stimulate LDL reecptor synthesis
What are the phases of cholesterol synthesis?
1) Acetyl CoA -> HMG CoA
2) Conversion of HMG-CoA to squaline
HMGR is the rate limiting enzyme in cholesterol synthesis
3)
How does cholesterol degradation work?
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
What is the most important cholesterol related mechanism?
Production of bile acids in the liver
Cholesterol -> 7-alpha-hydroxycholesterol
via cholesterol-7-hydroxylase (rate limiting enzyme)
How does bile acid synthesis work?
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
What do bile salts do?
Help lipid digestion and fat soluble vitamins absorption in small intestine
What is contained in bile?
Bile salts, cholesterol, phospholipids, bilirubin, biliverdin
Where do bilirubin and biliverdin come from?
Degradation products of heme
Most bile acids are conjugated with?
What effect does this have?
Glycine and taurine
Increases solubility
How does cholesterol homeostasis occur?
Cholesterol homeostasis occurs through
intricate regulation through cholesterol
synthesis, LDL receptor activity, and bile
acid synthesis
How does cholesterol biosynthesis regulation occur?
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
What effects do hormones have on HMGR?
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
Describe sterol mediated changes in gene expression that affect cholesterol homeostasis
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
How does SREBP regulate expression?
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
