Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Biochemistry > Cholesterol Synthesis & Lipoprotein Transport > Flashcards

Cholesterol Synthesis & Lipoprotein Transport Flashcards

1
Q

Cholesterol

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Chole

A

Greek for bile

steros = solid

-ol = alcohol

origin of the name cholesterol

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

membrane permeability

A

cholesterol is a requirement for proper membrane permeability and fluidity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Steroid hormones

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

HMG-CoA

A

hydroxymethylglutaryl-CoA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

isoprene

A
  • product of step 2 in cholesterol synthesis (from mavolonate)
  • rubber and latex are compounds of isoprene
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

squalene

A
  • product of stage 3 cholesterol synthesis
  • 30C
  • precursor to:
    • cholesterol in animals
    • stigmasterol in plants
    • ergosterol in fungi (inh by Ketoconazole, an antifungal drug)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

HMG-CoA reductase

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

familial hypercholesterolaemia

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

chylomicrons

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

VLDL

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

LDL

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

HDL

A
  • 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)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

lipoprotein

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Cholesterol made in the liver is

A

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 well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

How is Acetyl-CoA transported across the mitochondrial membrane into the cytosol for cholesterol synthesis?

A
  • ACoA combines w/oxaloacetate –> citrate (part of Krebs)
  • citrate via transporter –> cytosol
  • undergoes reverse reaction –> ACoA + oxaloacetate
  • NADPH generated drives the synthetic pathway
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What is the clinical target of cholesterol synthesis for regulation of its production?

A

HMG-CoA reductase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What is stage 1 of cholesterol synthesis from A-CoA?

A

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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What is stage 2 of cholesterol synthesis from A-CoA?

A

Mevalonate –> activated isoprene (5C)

  • consumes 3 ATP
  • loss of CO2 + phosphate group
  • rubber and latex are compounds of isoprene
20
Q

What is stage 3 of cholesterol synthesis from A-CoA?

A

isoprene (5C) to squalene (30C)

21
Q

What is stage 4 of cholesterol synthesis from A-CoA?

A

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
22
Q

ApoA-I

A
  • in HDL
  • activates LCAT (lecithin cholesterol acly transferase), makes esters
23
Q

ApoC-II

A
  • on chylomicrons, VLDL, HDL
  • activates lipoprotein lipase (breaks down TG for use in cells)
24
Q

How is fat metabolised into the different types of cholestrol?

A
  • 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
25
Q

LCAT

A

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
26
Q

ACAT

A

acyl-CoA-cholesterol acyl transferase

  • in liver cells
  • helps VLDL formation:
    • forms cholesteryl esters from pure cholesterol and fatty acyl CoA
27
Q

What is considered a high blood cholesterol level?

A

plasma cholesterol > 5.5 mmol/L

28
Q

What causes thrombus formation in atherosclerosis?

A

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)

29
Q

Describe how LDL is taken up by liver cells

A

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
30
Q

Statins

A
  • 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
31
Q

What is the mechanism of ezetimibe in treatment of hypercholesterolaemia?

A
  • inhibits cholesterol absorption
    • binds to a sterol transporter in the intestine
    • does not affect absorption of bile acids or fat solubel vitamins
    • lowers LDL
32
Q

What are the possible side effects of ezetimibe?

A
  • diarrhea
  • headache
  • tiredness
  • allergic reactions
  • severe joint or stomach pain
33
Q

How can ezetimibe be prescribed to lower cholesterol?

A
  • 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
34
Q

How can nicitonic acid/niacin reduce choleseterol?

A
  • 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
35
Q

What are the common adverse effects of niacin?

A
  • vasodilation
  • flushing (tolerance develops)
  • hypotension
  • nausea, vomiting (tolerance develops)
36
Q

What are the rare adverse effects of niacin?

A
  • itching
  • glucose intolerance
  • uric acid retention
  • increase hepatic impairment
37
Q

What is the mechanism of fibrates in hypertriglycerideaemia treatment?

A

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)
38
Q

What are the indications for fibrates?

A
  • adjunct therapy to dietary changes for high TGs
  • mixed hyperlipidaemia
  • 2nd line therapy for hypercholesterolaemia
39
Q

What are the precautions of using fibrates?

A
  • mild elevation of serum aminotransferase
    • marker of liver toxicity
    • monitor every 3mo
40
Q

What are the common adverse effects of fibrates?

A
  • nausea
  • dry mouth
  • headache
  • rash
41
Q

What are the rare adverse effects of fibrates?

A
  • arrhythmias
  • gallstones
  • photosensitivity
  • impotence
  • depression
42
Q

What are the Omega-3 fatty acids?

A

eicoapentanoic acid (EPA)

docosahexanoic acid (DHA)

in oily fish

43
Q

What is the benefit of Omega-3 fatty acids?

A

Reduce triglycerides and LDL

44
Q

What are the possible side effects of fish oils?

A
  • aftertaste, fishy burp
  • diarrhea, abdominal discomfort
  • blood thinning effect (tf affects coagulation)
45
Q

What is the polytherapy for severe hypertriglyceridaemia?

A
  • low fat diet
  • fibrates
  • fish oils
  • statins
  • niacin
  • orlistat (inhibits fat absorption from gut)
46
Q

Orlistat

A
  • 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
47
Q
A

Biochemistry (5 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions