Cholesterol Metabolism Flashcards
Major sources of liver cholesterol
- Dietary: taken up in chylomicron remnants
- Extrahepatic tissues: taken up into HDL
- De novor synthesis by liver
Major routes by which cholesterol leaves the liver
- Secretion of VLDL
- Free cholesterol secreted in bile
- Conversion to bile acids/salts
Cholesterol structure
- Four planar hydrocarbon rings: steroid nucleus
- Most cholesterol in the plasma is esterified to a fatty acid at carbon 3 (more hydrophobic).
Structural importance of cholesterol
- Component of cell membranes
- Increases mechanical strength
- Decreases permeability and fluidity
Polar portion of cholesterol
- Hydroxyl group
- Small size of polar group allows for a large amount of flipping of cholesterol
Sterols
- Cholesterol is the major form of sterols in animal tissue
- Four fused hydrocarbon rings and 8-10 carbons in the hydrocarbon tail attached to C17, and a hydroxyl at C3
Sitosterolemia
- Rare inherited autosomal recessive plant sterol storage disease
- Mutations in ABCG5 and ABCG8 genes which encode ABC transpoorters: sterolin 1 and sterolin 2
- Diminished pumping of plant sterols back into intestine
- Increased phytosterols in blood and tissues
- Tuberous xanthomas
- Propensity toward premature coronary atherosclerosis
Cells that synthesize cholesterol include
- Virtually all cells except RBCs in humans
- Majority by liver, intestines, adrenal cortex, and reproductive tissues
Carbon source for cholesterols
-Acetyl CoA
Reducing equivalent for cholesterol synthesis
-NADPH
Cholesterol synthesis location
- Cytoplasmic surface of smooth ER
- Requires ER membrane and cytosolic enzymes
Step 1 in cholesterol synthesis
- Acetyl CoA to HMG CoA: 2 carbons to 6 carbons
- 2 Acetyl CoA condense with loss of one CoA to form Acetoacetyl CoA (Thiolase enzyme)
- A third acetyl CoA molecule added by HMG CoA synthase (Cytosolic form) to form HMG CoA
Step 2 in cholesterol synthesis
- HMG CoA to Mevalonate: KEY REGULATORY STEP
- Catalyzed by HMG CoA Reductase: Integral membrane protein of smooth ER with catalytic domain facing cytoplasm
- Excess cholesterol inhibits HMG CoA Reductase
- 2 NADPH required as reducing agent
- CoA released: makes it irreverisble
Mevalonate to cholesterol steps
- Mevalonate to 5-pyrophosphomevalonate: 2 steps that transfer phosphate from ATP. Makes more water soluble.
- IPP formed by decarboxylation. Requires ATP.
- IPP isomerized to DPP: Isomerase
- IPP and DPP condense to form ten carbon GPP: Transferase
- Second molecule of IPP condenses with GPP to form 15 carbon FPP: Transferase
- Two FPP combine, release pyrophosphate, and reduced. Formed 30-C Squalene (total of 18 ATP used to make)
- Squalene to sterol lanosterol by ER associated enzymes using oxygen and NADPH
- Lanosterol to cholesterol. Multi step. ER associated process
HMG CoA Reductase Regulation- Transcriptional level
- Catalyzes HMG CoA to Mevalonate
- Regulation under control of SREBP-2 which binds SRE and is associated with SCAP.
- Low cholesterol: SREPB-2-SCAP complex moves to golgi and stimulates cleavage of SREBP resulting in an active transcription factor
- TF enters the nucleus and stimulates expression of HMG CoA reductase mRNA.
- High cholesterol: binds to sterol sensing domain of SCAP, and prevents the complex from moving to the Golgi.
HMG CoA Reductase Regulation- Post translational control
- Enzyme degradation
- High cholesterol binds to sterol sensing domain of reductase itself
- Trigger degradation of HMG CoA reductase and therefore decreased cholesterol biosynthesis
HMG CoA Reductase Regulation- Phosphorylation/dephosphorylation
- Phosphorylated: inactive
- Dephosphorylated: active
- ATP low, AMP high, inactive, decreased cholesterol synthesis
HMG CoA Reductase Regulation-Hormonal
- Insulin and thyroxine upregulate
- Glucagon and glucocorticoids down regulate
Statin drugs
- Structual analogs of HMG
- Competitive inhibitors of HMG CoA Reductase
- Lower plasma levels of cholesterol (prevent synthesis)
Degradation of cholesterol
- Sterol nucleus eliminated from body by conversion to bile acids and bile salts
- Small amount excreted in feces or secretion into bile
- Some modified by bacteria before excretion
- Primary products made: isomers of coprostanol and cholestanol
Bile acids
- Steroid nucleus ring with two or three hydroxyl groups
- Half are protonated and half are deprotonated in the intestine
- Polar face and nonpolar face
Two most common primary bile acids
- Cholic acid: Three hydroxyl groups
- Chenodeoxycholic acid: Two hydroxyl groups
Bile acid synthesis
- OH groups added to sterol ring
- Double bond reduced
- Hydrocarbon chain shortened and carboxyl group introduced
- Rate limiting step: addition of hydroxyl group at carbon 7 of cholesterol: Cholesterol 7-alpha-hydroxylase (down regulated by bile acids)
Conjugated bile salts
- Bile acids conjugated to serine or taurine before leaving the liver
- Glycocholic and glycochenocholic acid and taurocholic and taurochenocholic acids formed.
- Better detergents than bile acids
- Only conjugated forms found in bile
Intestinal flora role with bile salts
- Bacteria in intestine can remove glycine and taurine from conjugated bile salts
- Can also remove hydroxyl group producing secondary bile acids
Secondary bile acids
- Deoxycholic acid
- Lithocholic acid
