Cholesterol Flashcards
Which 3 sources are fats derived from?
- Diet
- De novo synthesis
- Adipose tisse deposits (storage)
Which enzymes break down dietary fats?
Lipases
Where are bile salts made and stored?
- Liver
- Gall bladder
How do bile salts reach fats?
Bile duct to intestine
What is the function of bile salts?
Emulsify fats
What is an essential property of bile salts?
Amphipathic
- Hydrophobic 27C skeleton
- Hydrophilic hydroxyl groups
What does a lack of bile salts result in?
Steatorrhea (fatty stool)
What drug can be used to treat obesity and how?
Olistat
- Inhibitor of gastric and pancreatic lipases
- Dec fat absorption 30% —> excreted out
- Clinical trials show treat for up to 2 years
What are the side effects of orlistat?
Abdominal pain
Urgency to defecate
Inc flatus (farting)
Steatorrhoea
How is orlistat produced?
Chemically synthesised derivative of lipstatin (from Streptomyces toxytricini bacteria)
How are lipids transported and why?
Lipoproteins
- Lipids hydrophobic but lipoproteins amphipathic —> transportable in plasma
What are the 5 types of lipoproteins?
- Chylomicron
- Very low density (VLDL)
- Intermediate density (IDL)
- Low density (LDL)
- High density (HDL)
What is the source and role of chylomicrons?
- Intestines
- Dietary fat transport
What is the source and role of VLDLs?
- Liver
- Endogenous fat transport (synthesised fat)
What is the source and role of IDLs?
- VLDL
- LDL precursor
What is the source and role of LDLs?
- IDL
- Cholesterol transport
What is the source and role of HDLs?
- Liver
- Reverse cholesterol transport
What 3 parts do chylomicrons consist of?
- Triglycerides in core
- Phospholipid monolayer membrane
- Apoproteins embedded in membrane
Which cells absorb digested dietary products and where?
Enterocytes lining brush border of small intestine
Which system transports CMs to the bloodstream and what are the 4 steps?
Lymphatic
1. Lacteals of intestine
2. Thoracic duct
3. Left subclavian vein
4. Bloodstream
Where do CMs acquire apoproteins from?
HDL
How does lipoprotein lipase bind to CMs?
Binds to complimentary apoproteins
Where is lipoprotein lipase found?
Capillary endothelial cells lining tissues (adipose, heart, skeletal muscle)
What happens to the products of digested triglycerides?
- Fatty acids —> B-oxidation
- Glycerol —> gluconeogenesis in liver
What are the 5 stages of the cycle of a CM?
- Fat absorbed by enterocytes
- Chylomicrons synthesised in enterocytes
- Apoproteins added by HDL
- Lipoprotein lipase cleave chylomicron —> fatty acids to tissue and glycerol to liver
- Remnant chylomicron to liver (HDL adds apoproteins)
What is the function of cholesterol?
Regulate stiffness of cell membranes
Where is cholesterol found?
Cell membranes (90%)
What type of chemical is cholesterol?
Steroid
Why is cholesterol amphipathic?
- Hydrophobic C skeleton tail
- Hydrophilic hydroxyl group head
Why is most cholesterol in the body produced via de novo synthesis?
Limited intake via diet (0.5g/day)
What are the 3 stages of cholesterol synthesis?
- Synthesis of isopentenyl pyrophosphate (C5)
- Condensation of 6 to form squalene (C30)
- Cyclisation and demethylation
Where does each of the 3 stages of cholesterol synthesis occur?
- Cytoplasm
- Cytoplasm
- ER
What is the first reaction in the synthesis of isopentenyl pyrophosphate? (acetyl CoA start)
2 Acetyl CoA + H2O —> Acetoacetyl CoA + CoA
- B-ketothiolase
What are the 2nd and 3rd steps of isopentenyl pyrophosphate? (acetoacetyl CoA start)
- Acetoacetyl CoA + Acetyl CoA + H2O —> HMG-CoA + CoA
- HMG-CoA synthase - HMG-CoA —> Mevalonate + CoA
- HMG-CoA reductase
- uses 2 NADPH + 2H+ —> 2NAD+
-RDS
How is isopentenyl pyrophosphate synthesis regulated?
HMG-CoA reductase inhibited by mevalonate, cholesterol and bile salts (negative feedback)
What are the 4th, 5th, 6th and 7th steps of isopentenyl pyrophosphate synthesis? (mevalonate start)
- Mevalonate —> 5-Phosphomevalonate
- Mevalonate kinase (use ATP)
- Phosphorylation - —> 5-Pyrophosphomevalonate
- Phosphomevalonate kinase (use ATP)
- Phosphorylation - —> phosphorylated intermediate
- Kinase (use ATP)
- Phosphorylation - —> 3-Isopentenyl pyrophosphate
- Phosphomevalonate decarboxylase
- Decarboxylation
What are the 2 products final isopentenyl pyrophosphate synthesis?
- Isopentenyl pyrophosphate
- Activated isoprene
What are the 7 steps in stage 1 of cholesterol synthesis? (isopentenyl pyrophosphate synthesis)
- 2 Acetyl CoA —> Acetoacetyl CoA
- add Acetyl CoA —> HMG-CoA
- —> Mevalonate
- —> 5-Phosphomevalonate
- —> 5-Pyrophosphomevalonate
- —> phosphorylated intermediate
- —> 3-Isopentenyl pyrophosphate
What 3 reactions occur in stage 2 of cholesterol synthesis? (IPP condensation)
- Isopentenyl PP —> Dimethylallyl PP (C5)
- Isomerisation - Dimethylallyl PP + Isopentenyl PP —> Geranyl PP (C10)
- Condensation - Geranyl PP + Isopentenyl PP —> Farnesyl PP (C15)
What are the first 4 steps in stage 3 of cholesterol synthesis? (cyclisation and demethylation)
- 2 Farnesyl PP —> Squalene (C30) + 2Pi
- Squalene synthetase
- uses NADPH —> NAD+ + H+ - —> Squalene epoxide
- Squalene monoxygenase - —> Prosterol cation
- —> Lanosterol
How is lanosterol finally converted to cholesterol?
- More cyclisation
- 3 Demethylations
- add HCOOH + 2 CO2
What are the 3 main derivatives of cholesterol?
- Steroid hormones
- Vitamin D
- Cholesterol esters
What is the precursor of all steroid hormones?
Pregnenolone
What are the 5 classes of steroid hormones?
- Gluticosteroids
- Mineralcorticosteroids
- Androgens
- Estrogens
- Progestagens
How is pregnenolone produced?
Cholesterol —> Pregnenolone
- Desmolase
What is vitamin D synthesised from?
Cholesterol
What are the 4 steps of calcitriol synthesis?
- Cholesterol —> 7-Dehydrocholesterol
- —> Previtamin D3
- UV light - —> Vitamin D3 (cholecalciferol)
- —> Calcitriol
- Hydroxylation
What is the function of calcitriol?
Calcium regulation
What does a vitD3 deficiency cause?
Rickets (bowed legs)
What are the 2 primary bile salts?
- Glycocholate
- Taurocholate
How and where are bile salts produced?
Liver
- Hydroxylation and carboxylation of cholesterol
What are the 5 parts of a lipoprotein?
- Triglycerols in core
- Cholesterol esters in core
- Phospholipid monolayer membrane
- Apoproteins embedded in membrane
- Cholesterol embedded in membrane
Where are cholesterol esters synthesised?
Plasma
What reaction occurs to synthesise cholesterol esters?
Cholesterol + acyl chain of Lecithin
- LCAT enzyme (lecithin cholesterol acyl transferase)
just remember enzyme —> tells all about reaction
What are the 6 steps in the life cycle of lipoproteins?
- VLDL synthesised in liver
- VLDL into circulation —> broken down —> triglycerides released
- Lipid-depleted remnant —> IDL + apoprotein to HDL
- IDL + CE from HDL —> LDL
- LDL uptake by macrophages or liver
- HDLs take lipids and cholesterol from tissue back to liver (reverse transport)
What is the function of LDL?
Transport cholesterol to peripheral tissues
What is the function of HDL?
Transport cholesterol back to liver for use/disposal
Why is the HDL “good” and LDL “bad”?
- HDL lowers total serum cholesterol
- Elevated LDL levels can lead to atherosclerosis
What is Familial Hypercholesterolaemia?
- Genetically high cholesterol
- Lack functional LDLRs (receptors) —> cholesterol remains in circulation
- Inherited monogenic dominant disease
What is the difference between inheriting 1 vs 2 FH genes?
- Cholesterol 2-3x higher —> atherosclerosis in middle age
- Cholesterol 5x higher —> severe atherosclerosis and coronary infarcts in adolescence
What are the 6 steps of LDL endocytosis?
- LDL bind to receptor
- Endocytosis
- Uncoating of vesicle (clathrin)
- Vesicle fuse with endosome
- Endosome fuse with lysosome —> hydrolyse LDL
—> cholesterol free - Transporter LDL receptor buds of endosome and returned to membrane
How many classes of FH mutations are there?
5
What are the 5 different mutations that cause FH and how do they do this?
- Frameshift/deletion/promoter mutation —> no LDLR
- Coding region —> LDLR not transported
- N-terminus —> LDLR doesn’t bind to LDL
- Cytoplasmic domain —> LDL not in via endocytosis
- EGFP domain —> LDL not released from receptor + LDLR not back to cell membrane
Which 2 drugs can treat hypercholesterolaemia?
- Resins
- HMG-CoA reductase inhibitors (statins)
How do statins work to treat hypercholesterolaemia?
Competitive inhibitor of HMG-CoA reductase
- Similar shape to mevalonate —> binds to HMG-CoA reductase —> inhibits cholesterol synthesis
- Act in liver
- Lipitor
How do resins work to treat hypercholesterolaemia?
Bind to bile-acid cholesterol complexes —> prevents reabsorption by intestine
- Act in intestine
