Chapter VII:
Cholesterol metabolism
Dr. Sameh Sarray Hlaoui
- Atherosclerotic vascular disease: stroke, coronary artery disease
- Structural component of cell membranemodulating their fluidity.- Precursor of bile salts, steroidhormones (sex hormones,mineralocorticoides..) and fat solublevitamins (vit D).- Serve as component of lipoproteins.
Cholesterol
Cholesterol
n A sterol, found in all eukaryotic cells .
n 4 fused hydrocarbon rings (A-D) calledsteroid nucleus.
n Ring A contains an oxygen (as –OH) onC3.
n Ring B has a double bond between C5and C6.
n Eight carbon branched hydrocarbonattached to C17 of D ring
C27 H45 OH
n Most plasma cholesterol is an esterifiedform with a fatty acid attached at C3:cholestryl esters
n Esterification occurs mainly in liver
n Cholesterol is eliminated from the liver asunmodified cholesterol in the bile
orn it can be converted to bile salts that are
secreted into the intestinal lumen.
Cholesterol Synthesis
n Primary site: liver (~1g/d)n Synthesized from Acetyl CoA
n Cytoplasmicn Tightly regulated process
n Over accumulation and deposition in coronary arteries ®atherosclerosis.
Step 1: Formation of HMG-CoA
n Condensation of 2 acetyl-CoA
acetoacetyl-CoA by thiolase
n Acetoacetyl-CoA combines with third acetyl
CoA ® Hydroxymethyl-glutaryl-coenzyme A)
HMG-CoA (6C)
n catalyzed by HMG-CoA Synthase.
Step 2: Synthesis of Mevalonic Acid
n Key step in synthesis of cholesterol
n HMG CoA is reduced by 2 molecules of
NADPH in the presence of HMG-CoA
Reductase: producing mevalonate or
mevalonic acid
Step 3: Synthesis of isopententylPyrophosphate (IPP)
n Steps:
- Mevalonate is phosphorylated by 2sequential Pi transfers from ATP, yieldingthe pyrophosphate derivative.
- Decarboxylation ATP-dependent withdehydration yields isopentenylpyrophosphate (IPP).
- Isopentenyl Pyrophosphate Isomeraseconverts IPP in 3,3-dimethylallylpyrophosphate (DPP).
Consumption of 3 ATP molecules
isomerase
Step 4: synthesis of farnesylpyrophosphate (FPP)
nPrenyl Transferase catalyzes head-to-tail condensations:
nDimethylallyl pyrophosphate (DPP)
condenses with isopentenyl
pyrophosphate (IPP) to form geranyl
pyrophosphate (GPP) (10 C)
nGPP condenses with another IPP ®
farnesyl pyrophosphate (FPP) (15 C).
(10 C)
+
Farnesyl pyrophosphate
(15 C)
Step 5: Synthesis of Squalene & Cholesterol
n Squalene: combine of 2 FPP;(NADPH is a reducing agent)
n Catalyzed by Squalene Synthase
n Cholesterol Synthesis:n Formation of lanosterol by a
sequence of reactions that usemolecular oxygen and NADPH
n Through a series of 19 reactions andshortening of the carbon chain by 3(from 30 to 27), cholesterol is formedfrom lanosterol.
Regulation of cholesterol synthesis
Different types of control:
-HMG CoA reductase
-Hormonal regulation
-Transcriptional regulation
-Drugs
Control of HMG-CoA Reductase
Short-term regulation:-HMG-CoA Reductase is inhibited by phosphorylation, catalyzed by AMP-Kinase(which also regulates fatty acid synthesis)
Long-term regulation
n Feed back inhibition by cholesterol itself, oxidized derivatives of cholesterol(mevalonate…).
n Degradation within proteosome: HMG-CoA Reductase contains a sterol-sensing domain (SSD). When cholesterol level increase in cells, ubiquitin proteinwill be attached to SSD by ubiquitin ligase allowing recognition of HMG CoAreductase by proteosome.
-is a major control point.
2- Hormonal Regulation
n Insulin:
n Binds receptors on the membrane of liver cells.
n Insulin binding→ activation of HMG-CoA → increased cholesterol synthesis
n Glucagon:
n Binds specific receptors on the membrane of liver cells.
n Glucagon binding→ inactivation of HMG-CoA → decreased cholesterol synthesis.
3- Transcriptional Regulation:
The expression of the gene for HMG CoA is controlled by the transcription factor SREBP-2(Sterol regulatory element binding protein-2).
SREPB-2 is a protein of ER membrane, associate with another ER membrane protein SCAP (SREBP cleavage activating protein) and form a complex.
- When cholesterol level is low: the complex moves from ER to Golgi, where SREBP-2 is acted upon by 2 proteases which release domain of SREBP, that enters the nucleus, binds the SRE (sterol regulatory element) (in upstream of reductase gene), acts as transcription factor synthesis of HMG CoA cholesterol.
- When cholesterol is abundant, it binds SCAP at its sterol sensing domain (SSD) and induce the binding of SCAP to other membrane protein. Thus the SREBP-2 is retained in the ER membrane no activation of gene no cholesterol synthesis.
4- Drug Control: Statins
n Statins: (or HMG-CoA reductase inhibitors) are a class of drugs used to lower
cholesterol levels. They act as competitive inhibitors of HMG-CoA reductase:
They get “stuck” in the active site This prevents the enzyme from binding
with its substrate, HMG-CoA.
n Nb of statins are on the market: Statins Trade name
Atorvastatin Lipitor
Fluvastatin Lescol
Lovastatin Mevacor, Altocor
Pravastatin Pravachol, Selektine, Lipostat
Rosuvastatin Crestor
Simvastatin Zocor, Lipex
Degradation of Cholesterol
n Humans cannot degrade cholesterol to CO2 and H2O (we don’t have these enzyme mechanisms)
n Rather, the sterol nucleus is eliminated from the body by:
n Conversion to bile acid and bile salts
n Secretion of cholesterol into bile
Bile Acid/Salt Metabolism
n Major excretory form of cholesteroln Synthesized in liver, from cholesterol(27C) by loss of 3 carbons (24 C).
n Bile acid/salts involved in dietary lipid digestion as emulsifiers
n The double bond in cholesterol B-ring is reduced.
n 2 or 3 hydroxyl groups are added in thesteroid nucleus
n COOH at side chain
(3OH)
(2OH)
Types of Bile Acids/Salts
n Primary bile acidsn Good emulsifying agents
i. Cholic acid (3OH) ii. Chenodeoxycholic acid (2OH)
n Conjugated bile saltsn Amide bonds with glycine or Taurine (organic acid)n Very good emulsifier
BILE SALTSConjugation of bile acids in the liver with glycine or taurine produces bile salts:
Chenodeoxycholic acid (2OH)
The ratio of glycine to taurine forms in the bile is3:1
GlycocholicTaurocholic
Cholic acid(3OH)
BILE ACIDS
BILE SALTSGlycochenodeoxycholicTaurochenodeoxycholic
¨Bacteria in the intestine can deconjugate bile salts
Functions of Bile Salts
Ø Important for cholesterol excretion:
1. As metabolic products of cholesterol
2. As solubilizer of cholesterol in bile
Ø Emulsifying factors for dietary lipids, a pre-requisite step for efficient lipid digestion which facilitate intestinal lipid absorption.
Hormonal Control of Bile Secretion: Cholecystokinin (CCK)
Enterohepatic Circulation
n Most bile salts are reabsorbed by the liver: Enterohepaticcirculation.
n 5% will be lost in feces
CholelithiasisCholesterol Gallstone Disease
aDue to their deficiency, cholesterols crystals precipitate in the gall bladder resulting in cholesterol gallstone disease
aCauses:
Bile salts in bile:
THE END!