Molecular Biology - Cholestrol Flashcards
3 main sources fats are derived from
Diet
De novo biosynthesis in the liver
Storage deposits in adipose
What are deitary fats broken down by?
Lipases
Where are bile salts generated and stored?
Liver and gallbladder respectively
Bile salts during digestion?
Pass from bile duct into intestine where they emulsify fats in the intestine, aiding their digestion and absorption of fats + fat-soluble vitamins
Lack of bile salts
Majority of fat passes through undigested resulting in steatorrhea (fatty stool)
Treatment for obesity
Orlistat is a gastric/pancreatic lipase inhibitor and derivative of lipstatin so reduces fat absorption
What type of lipoprotein has a role in dietary fat transport?
Chylomicrons - source is in the intestine
Anatomy of chylomicron?
Single phospholipid bilayer with apoproteins on outside and triglycerides in the middle
How is chylomicron created?
Digested dietary products are absorbed by enterocyte that line brush border ; triglycerides are resynthesized and transported via lymphatics
When do chylomicrons aquire apoproteins?
From HDL following release into bloodstream
Mechanism of action of chylomicron on heart/adipose/skeletal?
Binds to lipoprotein lipase and the fatty acids undergo beta oxidation while glycerol is returned to liver for gluconeogenesis
Special about chylomicrons?
Hydrophilic outside
Hydrophobic core
What type of molecule is cholestrol
Steroid
Cholestrol uptake/amount needed?
All physiological requirements for cholestrol are supplied by liver through de novo synthesis of cholestrol from acetyl-coA
Cholestrol synthesis
1 pathway 3 parts
1) Cytoplasm - isopentyl pyrophosphate synthesis
2) Cytoplasm - 6 molecules of step 1 condensation to form squalene
3) ER - cyclisation/demethylation of squalene gives cholestrol
Step 1 of step 1
Needs two Acetyl CoA molecules condensation and releases coA
Main step of step 1
When creating mevalonate ; HMG-CoA reductase is negative feedback loop by end product cholestrol and mevalonate/bile salts
What happens in main step?
NADPH is oxidised to NADP and coA is removed
(redox)
To finish off step 1?
Sequential phosphorylation and decarboxylation
Second step?
3 condensation reactions of 5 carbon unit structures to make a C15 molecule ; two of which condense to form squalene
Step 3
Cyclisation + demethylation
how is cholestrol basis of all steroid hormones?
It producs the precursor called pregnenolone by enzyme desmolase
5 classes of steroid hormones?
Glucocorticoids
mineralocorticoids
androgens
estrogens
progestagens
What can vitamin D deficiency lead to?
Rickets
Synthesis of vitamin D
Exposure of skin to sunlight
Cholestrol and bile salts?
bile salts are major breakdown products of cholestrol ; glycholate and taurocholate
Source and role of VLDL
Liver ; endogenous fat transport
Source and role of IDL
VLDL and precursor to LDL
Source and role of LDL
IDL - cholestrol transport
Source and role of HDL
Liver - reverse cholestrol transport
Lipoprotein
Cholestrol esters and triacylglycerols in middle with single phospholipid bilayer outside containing apoproteins and cholestrol
Cholestrol to cholestrol ester
Synthesized in PLASMA from cholestrol and lecithin ; via catalyses of LCAT
VLDL synthesis
In liver and then released into circulation
HDLs synthesis
In liver and smal intestine and take up lipids/cholestrol from tissue back to the liver
IDLs syntehsis
Triacylglycerol removal from VLDL
LDLs synthesis
Cholestrol ester transfer from HDL to IDL
Bad vs good cholestrol
HDL = good cholestrol ; take cholestrol from peripheral tissue back to the liver for use/disposal and lower cholestrol levels
LDL = leads to atherosclerosis if prolonged elevation - transport cholestrol from liver to periphery
Bile acids?
Cycle between intestine and liver
Chylomicrons cycle?
Free fatty acids are released (to build up adipose tissue etc) and remnants are left over to then return to the liver
Familial hypercholestrolaemia
Monogenic dominant trait - they have serum that is 2/3 times the normal level and are susceptible to atherosclerosis (single copy of gene)
Those with both copies of mutant gene for FH
Severely affected 5* as much cholestrol and coronary infarcts/atherosclerosis in adolescence
Homozygous FH
Two faulty copies of mutant gene
Symptoms of FH
Xanthomas lying superficially ; deposition of LDL-derived cholestrol
Fibroblast
Contributes to formation of connective tissue
In FH what happens to the fibroblasts
THEY LACK LDL RECEPTORS SO UNABLE to take up cholestrol
LDL endocytosis?
Endocytosis
Uncoating
Fusion with endoscope (and subsequent lysosome breakdown)
Budding off vesicles
Return of LDL receptors to membrane
How to control FH using statins?
Statins like lipitor has similar structure as mevalonate so end product inhibition of HMG-CoA reductive preventing synthesis of cholestrol
Mode of action of Resins?
Bind to bile acid-cholestrol complexes preventing reabsorption by the intestine
