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CELL II > Lipid Transport > Flashcards

Lipid Transport Flashcards

1
Q

Where are lipids transported from?

A
  • gut to liver
  • liver to non-hepatic tissue including adipocytes
  • non-hepatic tissue back to liver
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2
Q

Fats + lipids in circulation?

A 
Triacylglycerols (45%)
Cholesterol esters Cholesterol (15%)
Phospholipids (35%)
Free FA (5%)
% in plasma varies with nutritional state
All are insoluble in water
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3
Q

How polyunsaturated FA are ligands for transcription factors involved in energy metabolism?

A

Role in regulation of insulin metabolism :
increase lipid oxidation in liver + muscle
decrease genes involved in lipogenesis in liver + adipose tissue
-Increase expression of UCP-2 + 3 in mitochondria to increase thermogenesis

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4
Q

Features of FFA?

A
  • Formed from triacylglycerides stored in adipose tissue
  • Circulates bound to protein as Na+ particularly albumin as unbound FA acts as a detergent
  • Saturation occurs at about 2mM FA molecules
  • FA enter cells by simple diffusion
  • Intracellular concentration FFA kept low
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5
Q

Features of lipoprotein?

A

-Carried in blood as plasma lipoproteins
-5 types of lipoprotein :
chylomicrons
very low density lipoproteins (VLDL)
intermediate density lipoprotein (IDL)
low density lipoproteins (LDL)
high density lipoproteins (HDL)
-Each particle has diff function

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6
Q

Functions of apolipoproteins / apoproteins?

A

-Structural = form substrate in which lipid can be constructed
-Solubilise lipids = so body transports a difficult class of
molecules
-Act as enzymes or enzyme cofactors (co-enzymes) :
Apo C2 activates lipoprotein lipase
ApoA1 for lecithin:cholesterol acyltransferase
-Tissue targeting :
Apo B100 + Apo E binds LDL receptor
Apo E binds HDL receptor

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7
Q

Lipoprotein composition?

A 
Chylomicrons : B48, Apo C2, C3, E
VLDL : B100 Apo C1, C2, C3, E
(VLDL made in liver released with only B100 when circulates it gets Apo C + E from HDL)
IDL : B100, Apo E
LDL	: B100	
HDL	 : Apo A1, A2, C1, C3, D, E
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8
Q

Describe how dietary lipids travel?

A
  • in gut triglycerides -> FA + monoacylglycerols via lipases
  • pass from gut lumen into gut epithelial cells
  • converted back into triglycerides
  • triglycerides assembled into chylomicron with other lipids (phospholipids, cholesterol) + proteins.
  • chylomicrons released into lymphatics
  • carried via thoracic duct to SVC
  • so dietary fats avoid direct delivery to liver + made available to extrahepatic tissue (diff to digested proteins, carbs which released into portal vein, delivered directly to liver
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9
Q

Features of dietary lipids?

A
  • Low density due to high TG
  • Apo C2, C3, E, B48 added in SER
  • Secreted by reverse pinocytosis in to lymphatics
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10
Q

Features of chylomicron?

A
  • Content reflects meal composition
  • Low density due to TAG
  • Contain fat-soluble vitamins A + E
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11
Q

Describe circulation of chylomicron

A

-circulate for 1hr but half-life of TAG only 5min
-so modified by lipoprotein lipases in circulation
-breaksdown TAG –> uptake of FA by tissues
-in circulation density increases as TAG removed - chylomicron remnants
-removed by liver by interaction of Apo E with
receptors on hepatocytes

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12
Q

Role of vit E?

A

antioxidant preventing oxidation of lipids which are associated with heart disease

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13
Q

Describe how lipoprotein lipase (LPL) works

A
  • expressed on top of endothelial cells
  • binds to + activated by Apo C2 on lipoprotein
  • TG broken down + diffusion across membrane of FFA across membrane
  • continues as chylomicron circulates
  • gains density
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14
Q

What’s LPL on adipocytes stimulated by?

A

insulin

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15
Q

Diff types of hyperlipidaemia?

A
  • Type 1: Def in lipoprotein lipase or Apo C2 + characterised by high plasma triglyceride
  • Type 2: Genetic defect in synthesis, processing or function of LDL receptor + characterised by high LDL
  • Type 4: Most common form –> raised VLDL conc due to obesity or alcohol abuse
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16
Q

Role of VLDL

A

transport lipids derived from liver around body

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17
Q

Role of chylomicrons?

A

transporting exogenous lipids from gut around circulation

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18
Q

What are VLDLs?

A

-synthesised in liver ER + golgi
-released with B100 + acquire Apo E, C2 from HDL
-interact with endothelial layer + metabolised by LPL
-remnant removed by liver by apoE (TG half life 15-60 min) :
60% VLDL remnants removed by liver
40% removed by adrenal + gonadal tissue (cholesterol used for hormone production) using B100 to bind to LDL
If excess LDL, receptors saturated + excess removed via low affinity scavenger receptor

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19
Q

What are VLDLs formation enhanced by?

A
  • Excess dietary carb
  • Circulating FFA
  • Alcohol enhances VLDL synthesis so increases lipid transport
  • Insulin + decreased glucagon
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20
Q

Describe process of VLDL

A

-VLDL released as nascent particle
-acquires ApoE + ApoC-2 from HDLs
-form mature VLDLs
-circulate + acted upon by LPL
-FA enters tissues + get smaller
-2 pathways :
~return to liver as VLDL remnants – removed by ApoE (50%)
~converted into IDLs via removal of more TGs
in liver sinusoids IDLs -> LDLs
LDLs taken up by liver + removed or taken up by non-hepatic tissue via interacting with LDL receptor

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21
Q

Role of LDL?

A

carrier of cholesterol

22
Q

What are LDLs?

A
  • Metabolised slowly 3 days
  • Carry cholesterol to periphery + regulate de novo synthesis of cholesterol via B100 binding to specific receptor on hepatocyte
23
Q

Role of HDL?

A

reverse cholesterol transport

  • take up circulating cholesterol from VLDLs, dead, dying cells
  • take cholesterol back to liver + steroid producing cells
24
Q

How are HDLs made?

A

in liver + intestine by budding from VLDL + chylomicrons

from free ApoA1

25
Q

Sig of receptor-mediated endocytosis?

A
  • Lipoproteins removed from circulation by receptor-mediated endocytosis
  • Lipoproteins act at specific tissues via receptor-mediated endocytosis
26
Q

Features of HDLs?

A
  • Circulating reservoir of apolipoproteins (C2 + ApoE)
  • Contain lectin cholesterol acetyltransferase (LCAT) which esterifies cholesterol
  • HDL binds to lipoproteins + cells via ApoE - vital for cholesterol transfer
27
Q

Good vs bad cholesterol?

A

HDL is good cholesterol
LDL is bad cholesterol
HDL/LDL ratio assesses susceptibility to heart disease
Normal ratio is 3.5

28
Q

Describe uptake of LDLs?

A
  • LDLs in circulation bind to specific receptors expressed on endothelial cells
  • receptor + LDL is endocytosed
  • vesicle fuses with endosomes
  • endosomes contain enzymes for breakdown of protein + metabolism of lipids
  • receptor goes off + re-inserted into membrane
  • further fusion with lysosome so more hydrolytic enzymes
  • receptor + apoliprotein broken down
  • forming AA, phospholipids, FFA, triglycerides to give lipids
  • cholesterol esters stored + utilised
29
Q

What regulates cholesterol uptake + synthesis?

A

Amount of cholesterol in the cell itself by amount that it uptakes + amount cell is making itself :

  • ↓ cholesterol = more LDL receptor expressed
  • ↑ cholesterol = inhibits HMG-CoA reductase (rate-limiting step in cholesterol synthesis) - target for therapy
30
Q

What effect does an increase in HMG-CoA reductase have on expression of LDL receptors?

A

-synthesis of LDL receptor + expression negatively regulated by intracellular conc of cholesterol
-↓ intracellular conc of cholesterol –> less cholesterol synthesis from ACoA so LDL receptor increase (HMG-CoA reductase is rate limiting step in cholesterol synthesis

31
Q

Describe effect of statins on cholesterol

A
  • inhibit HMG-CoA reductase (as it’s a competitive inhibitor: same Vmax but Km increased)
  • decrease cholesterol synthesis within cells
  • increase in synthesis + expression of LDL receptor
  • increase LDL-cholesterol uptake
  • lower circulating cholesterol
32
Q

Features of scavenger receptor?

A
  • Present on endothelial cells, macrophages, VSMC
  • Low affinity active when plasma LDL high or oxidised
  • Not regulated by cholesterol
33
Q

Role of Apo100?

A

present on VLDL and LDLs + bind to LDL receptor for uptake

34
Q

Role of ApoE?

A

present on VLDL, HDL, chylomicrons + allow removal from circulation (by specific tissues)

35
Q

Where’s LDL receptor present?

A

VLDL, LDL

36
Q

Where’s LDL-like receptor present?

A

VLDL, LDL, chylomicron

37
Q

Where’s scavenger receptor present?

A

LDL

38
Q

Affinity of LDL receptor?

A

high

39
Q

Affinity of LDL-like receptor?

A

high

40
Q

Affinity of scavenger receptor?

A

low

41
Q

What does LDL receptor bind to?

A

ApoB100

42
Q

What does LDL-like receptor bind to?

A

ApoE

43
Q

What’s LDL receptor regulated by?

A

cholesterol

44
Q

What’s LDL-like receptor regulated by?

A

cholesterol

45
Q

What’s scavenger receptor regulated by?

A

unregulated

46
Q

Tissue distribution of LDL receptor?

A

liver

47
Q

Tissue distribution of LDL-like receptor?

A

liver

48
Q

Tissue distribution of scavenger receptor?

A

endothelial cells, macrophages

49
Q

Loss of LDL receptor function?

A
  • Familial Hypercholesterolemia (FH)
  • Homozygous individuals:
    1. High serum cholesterol (800mg/ml, normal is 200mg/ml)
    2. Atherosclerosis
    3. Die young from heart attacks
    4. De novo synthesis is not regulated by LDL (as cell thinks it has less cholesterol)
  • Single AA substitution prevents localisation of LDL receptor to coated pits
50
Q

Role of scavenger receptors?

A

take up LDL from plasma when elevated but only active when circulating levels of plasma LDL very high

51
Q

Regulation of lipoprotein?

A

-Hormonal regulation : insulin, cortisol, thyroid hormones
-Nutritional status :
decreased synthesis during fasting
increased by dietary fats – unsaturated fats
-LDL expression : oestrogen

52
Q

Abnormalities of lipid transport?

A

-DM :
increased FFA mobilisation
decreased chylomicron + VLDL utilisation
-Gene defects : apolipoproteins, enzymes or receptors leading to hypercholesterolaemia, atherosclerosis
-Obesity : hypertension, NIDDM, hyperlipidaemia, hyperglycaemia

CELL II (9 decks)

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