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CPR Exam 1 > Lipids and Lipoproteins > Flashcards

Lipids and Lipoproteins Flashcards

1
Q

what are the features of Isoprenoids

A

-three acetyl CoA (a 2 compound acetyl CoA) to generate a IPP (isopentenyl pyrophosphate) a 5 C compound

IPP which serves as a building block for synthesis of all isoprenoids

these include steroids, lipid soluble vitamins, ubiquinone, and prenyl groups to anchor proteins to Plasma membranes

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2
Q

what are the sources of Acetyl CoA

A

generated in Mitochondria via

  • pyruvate
  • fatty acids
  • Amino acids

then transported to cytoplasm via the citrate shuttle

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3
Q

what is the back bone of steroids

A

six units of IPP to make a tetracyclic sterane ring

serves as back bone of steroids

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4
Q

what is the structure of cholesterole

A

Allicyclic compound made of 4 fused rings

has 27 carbons

and one hydroxyl group at C 3

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5
Q

characteristics of cholesterol

A

found in Plasma membranes and things like bile acids and bile salts, vitamin D, steroid hormones (progesterone, aldosterone, cortisol, testosterone, estradiol)

cells cant degrade steroid nucleus of cholesterol

must be used biochemically or excreted by liver, Excess cholesterol can lead to athersclerosis

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6
Q

how much cholesterol is produced

A

0.75 - 1 gram made in the liver but also in small intestine, adrenal cortex, ovaries, testes, and skin’

biosynthesis inversely proportional to dietary intake

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7
Q

what does cholesterol need to be made

A

18 acetyl CoA 18 ATP 16 NADPH and will finish with 27 carbons

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8
Q

Phase 1 of making cholesterol

A

Acetyl CoA

Acetoacetyl CoA

HMG CoA
-enzyme used to make this is HMG CoA synthetase

Mevalonate
-enzyme used to make this HMG CoA reductase (rate limiting step)

then to IPP

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9
Q

Phase II of making cholesterol

A

IPP to make Squalene

lanosterol

cholesterol

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10
Q

what inhibits HMG CoA reductase and some side effects

A

Statins used to lower amount of cholesterol
-lovastatin, simvastatin, pravastatin, atorvastatin

can lower up to 60 percent of cholesterol

very strong competitive inhibitor

  • Ki is 5-45 nM compared to natural 4 uM
  • binds in cytosol of the catalytic domain

also has a hypocholesterolemic action by increasing SREBP maturation to increase transcription of LDL receptor and help clear cholesterol in blood via LDL mediated endocytosis

Myotoxic side effects: duue to inhibit production of IPP which is important in the production of ubiquinone (CoQ) impairing mitochondrial function and then degeneration of myocytes
-can supplement this though

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11
Q

what is the fate of cholesterol

A

cholesterol is esterfied to cholesterol esters by the enzyme Acyl CoA cholesterol acyltransferase (ACAT)

then is packaged into VLDL and released into the blood to go to various organs to be used

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12
Q

what is the regulation on Cholesterol synthesis

A

regulated at rate limiting step

  • Direct inhibition by free fatty acids, bile acids, and statins
  • Covalent modifications: enzyme is inactive when phosphorylated and activated when dephosphorylated

in low energy, high AMP, activate AMPK will phosphorylate HMG CoA reductase

  • insulin will activate HMG CoA reductase
  • glucagon will deactivate HMG CoA reductase

also is controlled by transcription, translational , and post translational

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13
Q

Mechanism of Transcriptional control

A

HMG CoA reductase has a sterol regatory element in its promotor region

  • SREBP (binding proteins) in inactive form
  • activates SCAP (SREBP clevage activating protein
  • in presence of cholesterol, SREB-SCAB complex will be retained in ER due to binding of INSIG

-if low cholesterol, SREBP-SCAP complex will go to golgi and undergo proteolysis and mature to have SREBP translocate to nucleus to bind SBE to increase transcription of HMG CoA reductase

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14
Q

function, and structure of Lipoproteins

A

serve as vehicles for transport of cholesterol, cholesterol esters, TAGS, and fat soluble vitamins

outer layer: monolayer of phospholipids, free cholesterol, and apolipoproteins

inner core: packed with TAGS, cholesterol, cholesterol esters

  • lipoprotiens help transfer and deliver TAG
  • lipoproteins help with Cholesterol homeostasis
  • apolipoproteins Targeting signals/ligands
  • apolipoproteins activate various enzymes
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15
Q

what are the 5 different lipoproteins

A

Chylomicrons
Very low density lipoproteins (VLDL)
Intermediate density lipoproteins (IDL)
LOw density lipoproteins (LDL) (bad cholesterol)
High density lipoproteins (HDL (good cholesterol)

this is also same goes for size in that order

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16
Q

what 5 lipoproteins contains the most percentage TAGS?
cholesterol?
Proteins?

A

Chylomicrons have most TAGs but least protein

LDL: highest percentage of cholesterol relatve to size

HLDL: least TAGS but highest protein make up

17
Q

structures found on a chylomicron and its properties

A

ApoB-48 : facilitates transport
ApoC-II : activates capillary lipoprotein lipase
ApoE: facilitates uptake into liver

Exogenous and formed from dietary fats

  • largest
  • least dense
  • High TAG
18
Q

structures found on VLDL and properties

A

ApoB-100: uptake into cells
ApoC II: activates capillary lipoprotein lipase
ApoE: facilitates uptake into liver

  • made in liver
  • packaged with TAGs and cholesterol
19
Q

structures found on IDL

A

ApoB-100: uptake into cells

ApoE: facillitates uptake into liver

20
Q

Structures found on LDL and properties

A

ApoB-100: uptake into cells

bad cholesterol

no TAGs

lots of cholesterol

21
Q

structures found on HDL and properties

A

ApoA-1: activates enzyme that esterfies cholesterol
ApoC-II: activates capillary lipoprotein lipase
ApoE: promotes uptake into hepatocytes

good cholesterol

  • smallest
  • most dense
  • high protein and phospholipid content
22
Q

Chylomicron processing

A

1) nascent chylomicrons are assembled with dietary lipids in the small intestine and transported through the lymp back to the blood stream
2) additional apoproteins are added to create a mature chylomicron (apoC-II and ApoE are supplied by HDL)
3) Capillary lipoprotein lipase hydrolyzes TAGs into glycerol and free fatty acids then ApoC-II is released back to HDL
4) remnants areendocytosed by the liver via binding to ApoE to its receptor

23
Q

Type I and III proteinemia

A

these affect either the ApoC-1, ApoE or the capillary lipoprotein lipase

24
Q

VLDL, IDL and LDL processing

A

1) VLDL are assembled in the liver and released into the bloodstream
2) Capillary lipoprotein lipase hydrolyzes TAGs into glycerol and free fatty acids then ApoC-II is released and now just IDL remains
3) Cholesterol in IDL is delivered back to the liver via binding ApoE to IDL receptors in liver cells

half of IDL lose more TAG via action of the hepatic lipoprotein lipase and then will lose ApoE to become LDL

4) LDL deliver their cholesterol load to the liver and peripheral tissue of ApoB-100 to LDL receptors on target cell

25
Q

how does LDL play a key role in cholesterol metabolism

A

LDL is the major carrier of cholesterol in blood

LDL can carry 1500 cholesterol ester molecules

shell has ApoB-100 which is recognized by receptors in target cells

role of LDL is to transport cholesterol to peripheral tissues and regulate the synthesis of cholesterol

26
Q

how does the uptake of LDL occur

A

receptor mediated endocytosis

ApoB-100 will bind onto an LDL receptor and then get brought into the endosome

then the LDL receptor will release the LDL in the endosome due to the change in the pH

one class of mutation that results in familial hypercholesterolemia generates receptors that are unable to release the LDL cargo

27
Q

HDL processing

A

1) nascent HDL is synthesized in the liver and the small instestine
2) picks up cholesterol from peripherla tissues
3) LCAT esterfies cholesterol and these will enter the HDL making it spherical

4) HDL receives ApoC-II and ApoE from chylomicrons
the HDL will transfer the cholesterol to VLDL, IDL, LDL in exchange for TAGS and phospholipids via the CETP (cholesterol ester transfer protein)

HDL delivers its cholesterol load to the liver

28
Q

Beneficial effects of HDL

A

High HDL correlates positively with reduced risk of CAD
-because important for maturation of chylomicrons by supplying ApoC-II and ApoE

plays an important role in reverse cholesterol transport by removing cholesterol from parts of tissues in the body and bringing them back to the liver
-scavenges and removes LDL-cholesterol from periphery and transports it to liver where it can be recycled and processed

antioxidant, anti-inflammatory, antithromotic, and nitric oxide inducing properties

HDL- C levels are increased by weight loss, excersise and smoking cessation

29
Q

what protein is important for reverse cholesterol transport and can be mutated

A

Cholesterol-transport protein in endothelial cells and macrophages, APCA1 (ATP-binding cassette transporter, subfamily A1)

loss of this leads to a disease called Tangier disease
-HDL deficiency and accumulation of cholesterol in macrophages and premature athersclerosis

30
Q

Type I familial hyperchylomicronemia

A

Deficiency in apoC-II or defective lipoprotein lipase

increase in Chylomicrons
increase in Triacylglycerol

31
Q

Type IIa and IIb familial hypercholesterolemia

A

LDL receptor is completely IIa or partially IIb defective

increase in cholesterol
increase in triacylglycerol: normal IIa and increased in IIb
increase in LDL
increase in VLDL for IIb

32
Q

Tangier disease

A

hypolipoproteinemia

defect in transporter that supports cholesterol pickup by nascent HDLs

decrease in HDL

33
Q

Type I hyperlipoproteinemia

A

Hyperchylomicronemia

inabillity to hydrolyze TAGs in chylomicrons and VLDL

cause: deficiency in capillary lipoprotein lipase or ApoC-II, an essential part of LPL complex and necessary for enzyme activity

Primary is an LPL deficiency manifiests in infancy

ApoC-II deficiency post adolescence

Plasma TAG levels are greater than 1000 mg/dL

creamy appearance of blood

clinical symptoms: abdominal pain, acute pancreatitis, cutaneous eruptive xanthomas

treatment = low fat diet

34
Q

Type II Hyperlipoproteinemia

A

familial hypercholesterolemia

causes: defect in LDL receptor resulting in uptake of LDL via receptor mediated endocytosis

increased cholesterol in blood

high LDL undergoes oxidation, oxLDL leads to an inflammatory response leading to cardiovascular disease such as athersclerosis

impaired abillity to reckognize ApoB-100 on LDL

normal cholesterol = 130-200
heterozygous = 300-500
homozygous = >800

untreated lead to death of CAD

physical symptoms: Xanthomas, corneal , deposits in eyes, and angina pectoris

Heterozygous respond to diet, statins, and bile binding resins

Homoygous: LDL apheresis and liver transplant

35
Q

Plasma Cholesterol and Athersclerosis

A

LDL-C levels correlate positively with Cardiovascular disease
LDL-C accumulates nder the endothelial cells lining blood vessels
-there the LDL will modify to become oxidized LDL
-this oxLDL accumulates in the vessel wall and lead to endothelial injury leading to even more influx of LDL into arterial wall

this increased vascular permeabillity and leukocyte adhesion

  • oxLDL initiates an inflammatory response
  • macrophages up take the ox LDL but become engorged forming foam cells

Foam cells become trapped in the walls to form plaques
-death of foam cells, platelet adhesion, and recruitment of smooth muscle cells leads to further development of arterial plaque that eventually leads to athersclerosis

narrowing of arteries by the plaques lead to heart attacks

CPR Exam 1 (26 decks)

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