Cholestero, Lipoprotein Metabolism And Steroids Flashcards
Steroids
-organic compound with the four fused rings arranged in a specific configuration (ABCD ring system)
What is the ring arrangement of the steroids?
ABCD
Sterols
A subgroup of steroids with a hydroxyl group at a the 3-position of the A ring
Steroid + OH
Cholesterol
- highly hydrophobic compound
- the major sterol in animal tissues
Sterol + hydrocarbon tail
Steroid nucleus
The 4 ring structure shared by all steroids
What is an essential structural component of all animal cell membranes ( ~30%)?
Cholesterol
Cholesterol function
- essential membrane structural component
- required to maintain both membrane structural integrity and fluidity at different temps (flexibility)
- enables animal cells to dispense with the cell shape in order to protect membrane integrity and cell viability
- components of lipid rafts
Cholesterol is a precursor for the synthesis of
- bile salts
- steroid hormones
- vitamin D
What types of cholesterol are there?
Esterified and unesterified
Unesterified cholesterol
- free cholesterol
- what we normally refer to
- found in the membranes of all animal cell membranes
Esterified cholesterol
- cholesteryl esters
- form in which it is put in lipoprotein particles that go into plasma
- not found in the membranes
- most of the plasma cholesterol is in this form
What cells can synthesize cholesterol?
Almost all of the
What is the central organ for synthesis, distribution, and elimination of cholesterol?
Liver
What organs contribute most significantly to the overall cholesterol pool?
- liver
- intestine
- steroidogenic tissues
Sources of liver cholesterol
- Diet (delivered from chylomicron remnants)
- Delivered via HDLs (reverse cholesterol transport)
- De Novo synthesis
Routes for cholesterol clearance from the liver
- secretion into VLDL/LDL
- secretion of free cholesterol into the bile
- conversion to bile salts
What is the major route of elimination of cholesterol in the body?
Conversion to bile salts
Cholesterol balance
- No precise
- leads to gradual deposition of cholesterol in the tissues, especially the endothelial linings of blood vessels
Lipid depositions over time
- very slow process
- lead to plaque formation, causing narrowing of the blood vessels (atherosclerosis) and increased risk of cardio-, cerebro-, and peripheral vascular disease INCLUDING BLOCKING BLOOD SUPPLY TO THE EYE
- can be life threatening
Atherosclerosis
Narrowing of the blood vessels
Substrates for cholesterol synthesis
- acetyl CoA (builds carbon skeleton)
- reducing equivalents NADPH
- ATP is needed (produce energy)
*all need to be present together
When does cholesterol synthesis occur?
- in well fed state (when all substrates are available)
- when the cholesterol supply is low (VERY tightly regulated)
Cholesterol synthesis is…
- composed of multiple steps
- divided into 6 stages
Where does synthesis of cholesterol happen?
Hepatocytes
Stage 1 of cholesterol synthesis
Conversion of acetylene CoA to HMG CoA
-enzyme: HMG-CoA synthase
HMG CoA synthase
- Convert acetylene CoA to HMG CoA
- 2 isozymes in liver
- cytosolic of cholesterol synthesis
- mitochondrial for ketone bodies
What isozyme of HMG CoA synthase do we want for cholesterol synthesis?
Cytosolic
Stage 2 of cholesterol synthesis
Synthesis of mevalonate
- enzyme:HMG CoA reductive
- rate limiting key regulatory step
- irreversible
- integral membrane proline of ER facing the cytosolic
- inhibited by statin drugs (competitive inhibitor, lower LDL particles)
HMG-CoA reductive
Synthesis of mevalonate
Mevalonate
- synthesized in step 2 with HMG-CoA reductase
- integral membrane protein of ER facing the cytosol
- inhibited by statin drugs
What way does mevalonate face?
The cytosolic side of the rough ER
What is the rate limiting key regulatory step in cholesterol synthesis?
Synthesis of mevalonate from HMG-CoA reductase
What are the other 4 not so important steps of cholesterol synthesis?
- Conversion of mevalonate to isoprenyl pyrophosphates with loss of CO2
- Conversions of isoprenyl pyrophosphates to squalene
- Conversion of squalene to lanosterol
- Conversion of lanosterol to cholesterol
How many molecules of mevalonate are required to make one molecule of cholesterol?
6
-since each molecule of mevalonate requires 3 acetyl CoA, ultimately 18 molecules of acetyl CoA are required to make one molecule of cholesterol
How many molecules of acetylene Coa are required to make 1 molecule of cholesterol?
18
Are the steps in cholesterol reversible or irreversible?
Many of the steps are irreversible, and humans DO NOT have the enzymes to perform the reverse reactions
Can cholesterol be metabolized to CO2 like sugars and fats
No
Are the intermediates charged or neutral in cholesterol synthesis?
Neutral
-since the synthesis takes place in the cytoplasm, many of the intermediates are charged to make them soluble, until the formation of squalene (at this point the molecule is associated with carrier proteins)
What does any hydrophobic molecule need?
A protein carrier
Regulation of cholesterol synthesis via HMG CoA reductase
- Sterol-dependent regulation of the levels of the enzyme protein product
- Sterol-independent covalent modifications-phosphorylation/dephosphoryaltion
- Hormonal regulation
Sterol dependent regulation of the levels of the enzyme protein product
- enzyme gene transcription and expression (via SREBP transcription factor)
- enzyme degradation (via ubiquitination)
Sterol-independent covalent modifications-phosphorylation/dephosphorylation
Via AMPK reflecting the energy state of the cell
Hormonal regulation of cholesterol synthesis via HMG CoA reductase
-insulin and thyroxine upregulate HMG CoA reductase expression-glucagon and glucocorticoids downregulate it. (Stress/starvation)
Degradation of cholesterol
Ring structure CANNOT be metabolized to CO2 and H2O in humans
The intact sterol nucleus is eliminated by:
- Conversion to bile acids and bile salts
- Secretion of cholesterol into the bile
- Some of the cholesterol in the intestine is modified by bacteria before excretion
Bile
A watery mixture of ORGANIC and INORGANIC compounds by the liver to facilitate the digestion of lipids in the small intestine.
-Continuously produced and stored in the gallbladder
Bile salts
The major constituent of bile produced in liver cells from bile acids. 61%
Bile acids
Precursor for the synthesis of bile salts, produced in liver cells from cholesterol.
Formation of bile salts
Cholesterol > Bile acids > Bile salts
Bile salt circulation
Reabsorbed from the intestine and sent back to the liver to be used again (highly efficient)
What is the only significant loss of the steroid nucleus
Very small loss (>5%) as free cholesterol in the feces from the body under normal circumstances
Cholelithiasis
- gall stones
- form in the gall bladder where bile is stored
Origin of gall stones
-derived from cholesterol and result from too little bile salts and/or too much cholesterol in the gall bladder (the bile salts are required to solubilize free cholesterol)
Possible causes of gall stones
- inefficient enterohepatic cycling (bile salts not reabsorbed due to Ileal disease
- liver dysfunction (bile acid deficiency)
- other idiopathic reason
Lipoproteins
Spherical macro molecular complexes of lipids and specific proteins (apolipoproteins)
Function of lipoproteins
- to transport cholesterol, fats, and fat-soluble compounds to the plasma
- major transport system of lipid soluble vitamins
Types of lipoproteins
- chylomicrons
- VLDL
- LDL
- HDL
Chylomicron
-lipoprotein that transports dietary lipids, produced in enterocytes
VLDL
-lipoprotein that transports newly synthesized lipids produced in hepatocytes
LDL
Lipoprotein that transports cholesterol to the peripheral tissues
HDL
Lipoprotein that transports cholesterol from the periphery to the liver
-route if eliminating excess cholesterol
