Cholesterol Synthesis & Lipoprotein Transport Flashcards
Cholesterol
- waxy steroid metabolite found in cell membranes and transported in blood by lipoproteins
- important component of bile acids, steroid hormones, and vitamin D
- part of cell membranes
- principal sterol synthesized by animals
- synthesis in 4 stages
- initially isolated from gall stones in 1978
- 27C, greasy insoluble solid
-
4 fused ring structure (A, B, C, D)
- 3-OH is hydrophilic
- rest is hydrophobic and planar
- unique 5-6 unsaturated bond
- unique YVY tail at C17
Chole
Greek for bile
steros = solid
-ol = alcohol
origin of the name cholesterol
membrane permeability
cholesterol is a requirement for proper membrane permeability and fluidity
Steroid hormones
HMG-CoA
hydroxymethylglutaryl-CoA
isoprene
- product of step 2 in cholesterol synthesis (from mavolonate)
- rubber and latex are compounds of isoprene
squalene
- product of stage 3 cholesterol synthesis
- 30C
- precursor to:
- cholesterol in animals
- stigmasterol in plants
- ergosterol in fungi (inh by Ketoconazole, an antifungal drug)
HMG-CoA reductase
- hyperactivity can lead to ++cholesterol production and arteriosclerosis due to elevated blood LDL
- common clinical target for maintenance of cholesterol levels
- +fbk inhibits it by +breakdown of the reductase
familial hypercholesterolaemia
- pathology of cholesterol overload
- Nobel Prize: Goldstein & Brown, 1985
- inherited dominant disorder of mutations in the LDL receptor gene
- get atherosclerosis before pubery, MI mid-20s
- 1/500 heterozygous, 1/1mil in severe homozygous form
- homozygous form develops xanthomas - waxy plaques under skin on elbows, knees, buttocks; deosits on tendons and around cornea
- suspected in anyone with cholesterol levels > 15mM with a family history of early MI
- confirmed with analysis of LDL receptor gene
- treated with HMG-CoA reductase inhibitors - statins e.g. Lipitor
chylomicrons
- low proportion of free cholesterol and cholesteryl esters to TGs
- transporting TGs from fats in intestine
- deposit fat in mammary, muscle, and adipose tissues
- ApoC-II is recognized by receptors in these tissues
VLDL
- very-low density lipoprotien
- formed in liver
- low free cholesterol and cholesteryl ester content relative to TGs (less than chylomicrons, though)
- primarily delivers TG to tissues (mammary, muscle, adipose)
- remnants (IDL) either go back to liver or lose ApoC-II and retain ApoB-100 –> LDL
LDL
- highest ratio of cholesteryl esters to TGs and free cholesterol
- tf donates TGs to tissues (mammary, skeletal, adipose)
- ApoB-100 is recognized by LDL receptors on extrahepatic tissue or the liver
- LDL formed from VLDL in plasma
- some deposits TG into extrahepatic tissues
- some goes back to liver for repackaging
HDL
- structure solved in 2006-7
- low ratio of free cholesterol (~more than chylo), lowest ratio of TGs
- higher ratio of cholesteryl esters than chylo and LDL
- greatest protein and phospholipid content
- tf scavenges TGs from tissues
- formed when ApoA-I activates LCAT in tissues to take up cholesteryl esters
- acts on macrophages to stop them becoming foam cells (important in atherosclerosis)
lipoprotein
- contains lipids and proteins
- monophospholipid layer (containing unesterified cholesterol)
- hydrophobic lipid core (containing cholesteryl esters and TGs)
- carry cholesterol in the blood
- includes:
- chylomycrons
- VLDL
- LDL
- HDL
Cholesterol made in the liver is
Stored as cholesteryl esters for export in VLDL
- removal of polar 3-OH by ACAT (acyl-CoA-cholesterol acyl transferase)
Bile acids (polar detergent derivatives w/intact 3-OH)
- stored in gall bladder to emulsify fat
Membranes (8%)
- optimized for 37 deg C
- makes membrane less fluid
How is Acetyl-CoA transported across the mitochondrial membrane into the cytosol for cholesterol synthesis?
- ACoA combines w/oxaloacetate –> citrate (part of Krebs)
- citrate via transporter –> cytosol
- undergoes reverse reaction –> ACoA + oxaloacetate
- NADPH generated drives the synthetic pathway
What is the clinical target of cholesterol synthesis for regulation of its production?
HMG-CoA reductase
What is stage 1 of cholesterol synthesis from A-CoA?
acetate –> mevaolonate
- losing C=O
- transfer of 2C from CoA to another A-CoA by thiolase
- addition of another 2C from A-CoA by HMG-CoA synthase to produce HMG-CoA
- HMG-CoA reductase then converts it to Mevalonate
- driven by 2 NADPH
What is stage 2 of cholesterol synthesis from A-CoA?
Mevalonate –> activated isoprene (5C)
- consumes 3 ATP
- loss of CO2 + phosphate group
- rubber and latex are compounds of isoprene
What is stage 3 of cholesterol synthesis from A-CoA?
isoprene (5C) to squalene (30C)
What is stage 4 of cholesterol synthesis from A-CoA?
squalene –> cholesterol in endoplasmic reticulum
- removal of 3C
- final step catalyzed by 7-dehydrocholesterol reductase (DHCR 7)
- defect causes Smith-Lemli-Opitz syndrome
- in plants, get stigmasterol
- in fungi, get ergosterol
- antifungal ketoconazole inhibits this conversion
ApoA-I
- in HDL
- activates LCAT (lecithin cholesterol acly transferase), makes esters
ApoC-II
- on chylomicrons, VLDL, HDL
- activates lipoprotein lipase (breaks down TG for use in cells)
How is fat metabolised into the different types of cholestrol?
- FFAs absorbed in intestine –> TGs
- TGs packaged into chylomicrons –> bloodstream via lymphatics
- blood plamsa turns turbid after a meal
- mammary, muscle, & adipose tissue have ApoC-II receptors (chylo, LDL, HDL)
- take up TG, leaving chylo remnants –> liver
- liver packages VLDL
- mammary, muscle, adipose tissue w/ApoC-II
- take up TG, leave VLDL remnants (IDL)
- OR loses ApoC and retains ApoB-100 –> LDL
- LDL donates TG to extrahepatic tissues or returns to liver
- ApoA-I (liver and intestine, HDL precursor) scavenges cholesterol from extrahepatic tissues –> HDL, back to liver
LCAT
lecithin-cholesterol acyl transferase
- in plasma
- helps HDL scavenge cholesterol
- ApoA-I protein around HDL activates LCAT by binding to the tissue membranes
- accepts cholesterol (cholesteryl esters)
- HDL is then composed of cholesterol and phospholipid (lecithin) from the membrane
ACAT
acyl-CoA-cholesterol acyl transferase
- in liver cells
- helps VLDL formation:
- forms cholesteryl esters from pure cholesterol and fatty acyl CoA
What is considered a high blood cholesterol level?
plasma cholesterol > 5.5 mmol/L
What causes thrombus formation in atherosclerosis?
Ruptured plaques display tissue factor on foam cell membranes
this activates the extrinsic coagulation pathway
(exacerbated by decreased endothelial production of NO and prostacyclin/PGI2 which are anticoagulants and vasodilators)
Describe how LDL is taken up by liver cells
receptor mediated endocytosis
- nucleus produces 2 types of LDL receptors (one defective gene = only one functional receptor/half the amount on membrane e.g. FH)
- LDL R recognizes ApoB-100, promoting endocytosis
- endosome forms
- LDL receptor detaches –> membrane
- endosome fuses with lysosome
- LDL degrared to AA, FA, cholesteryl esters
- cholesteryl ester droplet -fbk HMG-CoA reductase to inhibit cellular synthesis of cholesterol
- in FH cells don’t take up the LDL
- tf get high circulating LDL
- cellular cholesterol production bc HMG-CoA reductase is not being inhibited
Statins
- competitive inhibitors of HMG-CoA reductase
- stop conversion of HMG-CoA to mevalonate –> -cholesterol
- e.g. Compactin, Simvastatin (Zocor), Pravastatin (Pravachol), Lovastatin (Mevacor), Rosuvastatin (Crestor), Atrovastatin (Lipitor)
- generally safe, but inhibit production of Ubiquinone, Q10 (in ETC) by inhibiting production of the precursor isoprene
- tf can cause skeletal and cardiac muscle complications that can lead to heart faulure (myopathy, myotoxicity)
- alleviated myotoxicity with Q10 supplements
- taken by 1/3 Australians over 50
- costs +$1b/year
- concerns: dispose to type II diabetes, dimentia
What is the mechanism of ezetimibe in treatment of hypercholesterolaemia?
- inhibits cholesterol absorption
- binds to a sterol transporter in the intestine
- does not affect absorption of bile acids or fat solubel vitamins
- lowers LDL
What are the possible side effects of ezetimibe?
- diarrhea
- headache
- tiredness
- allergic reactions
- severe joint or stomach pain
How can ezetimibe be prescribed to lower cholesterol?
- effective alone in statin-intolerant patients
- can be used in combination with all other lipid-lowering agents
- overcomes the ceiling effect of lowering LDL with statins
- can reduce dose of statins to minimize adverse effects
How can nicitonic acid/niacin reduce choleseterol?
- nicotinic acid = niacin = vitamin B3
- decrease VLDL from liver
- reduce plasma LDL and TG
- increases HDL
- lowers atherogenic lipoprotein A from LDL found in placques that inhibits thrombosis
What are the common adverse effects of niacin?
- vasodilation
- flushing (tolerance develops)
- hypotension
- nausea, vomiting (tolerance develops)
What are the rare adverse effects of niacin?
- itching
- glucose intolerance
- uric acid retention
- increase hepatic impairment
What is the mechanism of fibrates in hypertriglycerideaemia treatment?
e.g. gemfibrozil, fenofibrate
- agonists at nuclear receptors to regulate gene expression
- peroxisome proliferator activated receptor alpha
- increased synthesis of lipoprotein lipase (LPL)
- breaks down TG to FFA at tissue tf -plasma TGs
- moderately increases HDL
- variable effects on LDL (may increase tf not 1st line drug)
What are the indications for fibrates?
- adjunct therapy to dietary changes for high TGs
- mixed hyperlipidaemia
- 2nd line therapy for hypercholesterolaemia
What are the precautions of using fibrates?
- mild elevation of serum aminotransferase
- marker of liver toxicity
- monitor every 3mo
What are the common adverse effects of fibrates?
- nausea
- dry mouth
- headache
- rash
What are the rare adverse effects of fibrates?
- arrhythmias
- gallstones
- photosensitivity
- impotence
- depression
What are the Omega-3 fatty acids?
eicoapentanoic acid (EPA)
docosahexanoic acid (DHA)
in oily fish
What is the benefit of Omega-3 fatty acids?
Reduce triglycerides and LDL
What are the possible side effects of fish oils?
- aftertaste, fishy burp
- diarrhea, abdominal discomfort
- blood thinning effect (tf affects coagulation)
What is the polytherapy for severe hypertriglyceridaemia?
- low fat diet
- fibrates
- fish oils
- statins
- niacin
- orlistat (inhibits fat absorption from gut)
Orlistat
- used in obesity
- inhibits fat absorption in the gut by inhibiting lipase activity
- causes explosive diarrhea after a fatty meal
- can lead to behavioural modifications
