Cholesterol Metabolism Flashcards
(12 cards)
Structural properties of cholesterol
- Most abundant steroid of the body 240g per person
- Can be converted to other compounds such as bile salts, sex hormones, adrenal hormones and vitamin D
- Constitutes 25% of erythrocytes by mass
- Polar OH group gives weak ampiphillic (being hydrophilic and lipophilic)
- Fused rings provide rigidity
- In cell membranes cholesterol acts to broaden the temp range of order disorder transition, strengthening the cell membrane
- Broadening helps maintain the membrane fluidity
- Membrane fluidity is important to maintain protein function
Cholesterol formation and distribution (Mevalonate pathway)
- Most mammalian cells can synthesise cholesterol but only liver cells have substantial activity
- Around 100-300mg/dl in humans
- In blood lipoproteins cary cholesterol (and other lipids) to other cells
- The cholesterol can be derived form the liver and diets
- Statins can inhibit cholesterol biosynthesis and therefor reduce incidence of myocardial infarction
Formation (In liver)
Acetyl CoA–>Mevalonate–>Cholesterol
Cholesterol–>Cholesterol ester
Cholesterol–> bound to lipoproteins (transported to plasma)
Cholesterol–>Bile salts–>small intestine then reabsorbed by liver by enterohepatic circulation
Radioactive tracer studies show that cholesterol biosynthesis starts with (2C) Acetyl Coa and proceeds through (5C) Isoprenoid structures then (30C) squalene structures and finally (27C) cholesterol
Lipoprotein and reason for need
- Lipoproteins consist of chylomicrons, VLDLs, IDLs, LDLs and HDLs
- Cholesterol and phospholipids are only sparingly soluble
Chylomicrons and their duty
- Chylomicrons transport dietary exogenous cholesterol and Triacylglycerol from intestine to tissues
- Chylomicrons made in the epithelial cells within the villi of the duodenum
- Disposed of as remnants in the liver
VLDL, IDL, LDL
- Particles that transport endogenous cholesterol and triacylglycerol from liver to tissues.
- VLDL is exported from the liver and processed to IDL and LDL with apoproteins and fatty acids removed en route
HDL
- Transport endogenous cholesterol from tissues to liver
- Apolipoproteins of HDL are synthesised in the liver
Postulated scheme for synthesis, assembly and secretion of VLDL in a hepatocyte
1) Synthesis: The apoproteins, phospholipids, TAG, cholesterol and cholesterol esters are made in the endoplasmic reticulum
2) Assembly: These components are assembled into a prelipoprotein particle in the endoplasmic reticulum
3) Processing: The particle moves to the Golgi where additional phospholipids and perhaps cholesterol and cholesterol esters are added
4) Vesicle formation: A secretory vesicle containing the lipoprotein particles forms and fuses with the plasma membrane
5) Exocytosis: The VLDL is released into circulation
LDL function and structure
-LDL particle consists of 1500 cholesterol ester molecules surrounded by an amphiphilic coat of 800 phospholipids, 500 cholesterol and a single molecule of apolipoprotein b-100
Function of Acyl-CoA Cholestrol Actyltransferase
-Enzyme that is located in the endoplasmic reticulum that forms cholesterol esters from cholesterol
Catalyses the reaction
Acyl-CoA+Cholestrol–>CoA+cholestryl Ester
Enzyme belongs to the enzyme family of transferases, specifically actyltrasnferases, it participates in biosynthesis
Loss of cholesterol through excretion
- 30-60% of intestinal cholesterol absorbed
- Large quantities lost through bile salts as bile, non absorbed intestinal cholesterol and sebum
- 100mg lost in sebum
- 250mg lost as unabsorbed bile salts
- 550mg from desquamated (peeled off cells) cells
- 900mg must be obtained from a combination of synthesis and from diet
Atherosclerosis
- Formation of plaques in the blood vessels–>thrombus formation–>stenosis–>myocardial infarction
- Lesions begin as fairy streaks underlying the endothelium of large arteries
- Recriutment of macrophages and their subsequent uptake of LDL derived cholesterol are the major cellular events contributing to the initiation of atherosclerotic lesions
- Accumulation of lipids is required for the development of the plaque
- Lipid deposition probably starts with the movement of LDL from the blood into the vessel wall
Once within the wall 3 fates can befall LDL
1) May move back into blood stream - a process that may be facilitated by some lipid lowering strategies
2) It may become oxidised (through actions of free radicals\activity of leukocytes). Oxidised LDL is atherogenic
3) May be taken up by monocytes (macrophages –> foam cells). Foam cells become dangerous when they accumulate
HMG-CoA reductase and Statins
- Important enzyme in the Mevalonate pathway
- Mevalonate pathway can be stopped by statins by inhibition of HMG-CoA Reductase
- Statins therefor lower the amount of LDL cholesterol which can be attributed to aetiology of myocardial infarction.
