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ANAT365 > module 8 - metabolism > Flashcards

module 8 - metabolism Flashcards

1
Q

name 4 reasons why we need cellular trafficking to make and use energy

A
  • Hormone release from cells
  • Transport of energy into cells
  • Hormone receptor trafficking
  • storage and transport by fat (lipids)
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2
Q

what is metabolism?

A

chemical processes occurring within a living cell or organism that are necessary for the maintenance of life.

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3
Q

what is always the end product of metabolism?

A

ATP

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4
Q

what makes insulin? where are they? what % of organ?

A

B-cells: 1-2% of the pancreas

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5
Q

when is insulin secreted? what is it needed for?

A
  • secreted in response to high blood glucose
  • needed for taking up and storage of nutrients
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6
Q

where is insulin packaged?

A

in dense core granules DCGs in the GOLGI

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7
Q

what is needed in the membrane for vesicles to properly form at the membrane?

A

lipid rafts (cholesterol)

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8
Q

how is active insulin produced?

A

proinsulin is cleaved by proteases activated by acidic ph in vesicles

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9
Q

what part of proinsulin is cleaved off?

A

c-peptide (inactive subunit)

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10
Q

what enzyme cleaves proinsulin?

A

PC2

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11
Q

what do the insulin secretory vesicles look like?

A

fried eggs

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12
Q

what does glucose signal?

A

high nutrients!

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13
Q

how does glucose trigger insulin granules secretion?

A

glucose -> GLUT2 channel -> glucose get phosphorylated -> glycolysis -> oxidative phosphorylation -> ATP -> close Katp channels -> opens Ca channels -> signal for docked vesicles release

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14
Q

why does glucose get phosphorylated?

A

to stay trapped in the cell

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15
Q

more precisely what does production of ATP after glucose sensing cause?

A

closing of Katp channels, which increases membrane potential and opens voltage gated calcium channel

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16
Q

what is F-actin role in insulin secretion?

A

physical barrier: it gets reorganized after the first phase of secretion to allow more insulin vesicles to access the PM

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17
Q

apart from f-actin re-organization, what supports the second phase of insulin secretion?

A

microtubules transport of new insulin vesicles to the membrane

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18
Q

in what tissues does insulin control the entry and storage of glucose? via what transporter?

A

muscle and fat (biggest sink for circulating glucose) via GLUT4

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19
Q

characteristics of GLUT4

A

only open when glucose is abundant;
found in heart, muscle, adipose

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20
Q

what are the other glucose transporters? where are they found, how do they work?

A

GLUT2: in the brain, liver, pancreas
GLUT3: in the brain
They are always open, allows the tissue itself to sense glucose

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21
Q

what is the #1 important tissue where glucose must go?

A

brain

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22
Q

where is GLUT1 found?

A

adipose tissue

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23
Q

how does insulin control glucose uptake?

A

it stimulates recruitment of GLUT4 to PM via insulin receptors activation

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24
Q

where is GLUT4 stored when not needed?

A

GSVs, GLUT4 reservoir

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25
Q

what happens to glut4 when there is no insulin?

A

it cycles between endosomes and GSVs

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26
Q

the glut4 cycling between GSVs and endosomes allows what?

A

prevents blood glucose from getting too low

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27
Q

how many GLUT4 internalized pathways are there?

A

at least 2 which are tissue-specific

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28
Q

glucose uptake in ____ is very rapid which can lead to ______

A

muscles;
hypoglycemia

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29
Q

how can hypoglycemia be evitated?

A

by inactivation of insulin receptors by internalization and degradation, depending on trafficking machinery

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30
Q

in what situation must you shut down insulin signaling?

A

when you eat a lot

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31
Q

apart from decreasing insulin action, what are other purposes of insulin internalization?

A
  1. activate Ras/MAPK pathway to mitogenic endpoints (cell growth/proliferation)
  2. sustain liang-induced Akt phosphorylation (insulin target)
  3. go to nucleus, recruit IR complexes and affect transcription
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32
Q

what % of insulin is cleared from the circulation and degraded in endosomes? by what organ?

A

50%; by the liver

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33
Q

what type of diabetes develops after years of having too much insulin?

A

type 2

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34
Q

how can insulin receptors be involved in type 2 diabetes?

A

long-term insulin exposure may lead to receptor degradation instead of recycling, therefore less insulin receptor at cell surface, leading to insulin resistance

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35
Q

lipid droplets store fat in what form?

A

cholesteryl esters or acyl-glycerols (fatty acids bound to a glycerol backbone; mono, di ,triglycerides)

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36
Q

what is insulin’s effect on lipid?

A

stimulates lipid synthesis and storage

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37
Q

what are lipid droplets required for?

A

readily available source of energy during times of energy demand

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38
Q

what cells can store lipids?

A

all! but adipocytes and hepatocytes are better at it

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39
Q

how is the membrane of lipid droplets formed?

A

budding out of only the outer membrane of organelles, so the inside is hydrophobic

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40
Q

what do Rab proteins have to do with lipid droplets?

A

they appear to regulate interactions with specific organelles

41
Q

what happens to lipid droplets if you KO caveolin?

A

they can’t move or be catabolized (broken down)

42
Q

are all lipid droplets the same?

A

no they have different properties and functions

43
Q

what organelles are lipid droplets interacting with? (6)

A

ER, peroxisome, caveola, mitochondria, late endosome, early endosome

44
Q

what is the best hypothesis for lipid droplet formation?

A

accumulation of neutral lipid between the 2 layers of the ER membrane

45
Q

after formation, lipid droplets take up what? what happens to it after?

A

take up free fatty acid that are then broken down by lipases when needed for fuel

46
Q

name a few things lipid droplets can do

A
  • oscillate in restricted area
  • travel along microtubules
  • move to apical side to form milk fat
  • fuse via dynamin
  • fragment and disperse
  • spread in fungi
47
Q

what does chlamydia do to lipid droplets?

A

induces movement of LDs from cytoplasm into parasitophorus vacuole

48
Q

what does hepatitis C do to lipid droplets?

A

causes them to accumulate at microtubule organizing center

49
Q

give an example of how lipid droplets act as a cargo truck

A

transports kinases to activate lipolysis in fat, degradation of proteins, or lipophagy to eliminate misfolded proteins

50
Q

ribosomes and RNA have been found on LD surface, meaning that they may serve as what?

A

sites for protein translation

51
Q

what does an hepatitis infected liver look like?

A

has patches of huge lipid droplets

52
Q

hepatitis C virus HCV uses lipid machinery for what?

A

to traffic within the cell and replicate

53
Q

how does HCV enters the cell?

A

it hijacks lipoproteins receptors

54
Q

how does HCV replicate?

A

using lipid droplets as scaffold for viral assembly

55
Q

how does HCV spread?

A

it is secreted like lipoproteins (binds to lipoprotein)

56
Q

where in a lipid droplet can you find viral proteins and RNA? why?

A

on its surface; it can be transferred to the ER easily

57
Q

how does viral infection make lipid droplets bigger?

A

it increases lipid production and decreases lipid droplet turnover rate

58
Q

bigger droplets secrete more ______ therefore

A

lipoproteins (VLDL), therefore more HCV virus into circulation

59
Q

exosomes (extracellular vesicles): where are they thought to come from?

A

multivesicular bodies

60
Q

what do exosomes contain a lot of? why?

A

RNAs and miRNAs (miRNA is inhibitory);
they are protected in exosomes

61
Q

the IncRNA and miRNA cargo of EVs allow for what?

A

distant cells to influce gene transcipriton in other cell types

62
Q

ex of exosomes: what do cardiomyocytes secrete when their glucose is low?

A

exosomes that contain glucose transporters (GLUTs) along with the enzymes that metabolize glucose

63
Q

what happens to the vesicles secreted by cardiomyocytes in low glucose?

A

they are taken up by endothelial cells and promote the uptake of glucose from the blood, glucose metabolism, and pyruvate production

64
Q

what are risk factors for metabolic diseases?

A

Obesity, low/no exercise, diet, inflammation

65
Q

what are nanotubes?

A

tunnels connecting cells or organelles together through which mitochondria can travel

66
Q

inflammation in the body may triggers what relating to exosomes?

A

exosome secretion

67
Q

what are the 3 ways of mitochondrial therapy?

A

a) Endocytosis of mitochondrial-containing vesicles;
b) Transportation via actin-based tunnels;
c) absorption of exogenous mitochondria;

68
Q

what are the 2 hypothesis of the function of mitochondrial nanotunnels?

A
  1. sensing other cell’s intracellular environment
  2. mitochondria’s way of reaching out for help to improve metabolism or increase ration of healthy mito
69
Q

what did they discover in fish glands?

A

MAMs: mitochondria-associated-membrane (ER-mito interactions)

70
Q

what are MAMs characteristics?

A
  1. direct contact between mito and ER
  2. higher conc of lipids than ER or mito membrane
  3. unique lipid profile at connection points
  4. protein profile facilitating unique signaling, lipid synthesis, protein folding, thetering
  5. heterogenous
71
Q

what % of mito surface is involved in MAMs?

A

10 to 100%

72
Q

how did they isolate MAMs?

A

with a sucrose density gradient (easy since they have a special lipid structure)

73
Q

what are MAMs enriched with?

A

cholesterol and ceramides (PtEt, SM, GlcCer, P3)

74
Q

what happens to MAMs after depletion of cholesterol and ceramide lipids with detergent?

A

MAM proteins redistribute to the bulk ER, MAMs dissociate

75
Q

what proteins are contained by specialized MAM domains?

A

ER proteins – IP3R, calretuculin, CNX
Mito proteins – VDAC, p66shc
Unique proteins – FACL-4, Mnf2

76
Q

what kind of proteins (what function) are enriched in MAMs?

A

ion transport and cell signaling proteins:
- Ca2+ transport
- Apoptosis
- Metabolism
- Mitochondria dynamics & tethering

77
Q

what are proposed roles of MAMs?

A
  1. lipid reservoirs ex ceramides
  2. lipid metabolism, phospholipid synthesis
  3. enzyme platform for metabolism and cell growth
  4. mediate autophagy
  5. permit Ca2+ flow in mito
78
Q

What metabolic signals could benefit from these mito-ER interactions (MAMs)?

A
  1. skeletal muscle: requires tight calcium signaling, e.g. adrenergic signaling needed during exercise
  2. heart contraction: relies on mito and calcium concentrations for ATP
  3. insulin secretion: tighlty linked to Ca2+ calcium and ATP production
  4. liver: dysfunction involved in fatty liver
79
Q

what happens to MAMs in high cellular energy?

A

Akt (insulin target) breaks the MAM because don’t need more energy

80
Q

what is the question of the paper?

A

how do insulin receptors innbeta cells not get downregulated or have hyperactive insulin signaling if there is constant insulin in the ECM?

81
Q

how did they find Inceptor?

A

highly expressed gene in mouse embryonic pancreas

82
Q

what is inceptor structure?

A
  • growth factor receptor cysteine-rich domain
  • M6PR binding domain
  • TM helix
  • cytoplasmic tail
83
Q

inceptor has a similar structure as RTK receptors that do what?

A

RTK receptors desensitize

84
Q

what does inceptor not have?

A

intracellular signaling domain

85
Q

how does inceptor bind to clathrin?

A

AP2 domain

86
Q

where is inceptor found?

A

in pancreatic cells, not just insulin-producing beta cells

87
Q

what happens when you KO inceptor?

A

most mice die within 24h

88
Q

what are characteristics of baby mice lacking inceptor (lir-/-)?

A
  • low glucose (more glucose tolerant; got rid of injected glucose faster)
  • high insulin
  • more beta cells
  • hyperactive INSR and IGF1R
89
Q

what did they see when CKO inceptor in pancreatic beta cells with tamoxifen?

A
  • normal glucose and insulin fasting levels
  • CKO decrease glucose better over time
  • CKO are missing the 2nd phase of insulin secretion
  • CKO have bigger and more B cells
  • INSR and IGF1P are more phosphorylated (active)
  • Akt is more phosphorylated
90
Q

where did they localize inceptor?

A

mainly in Golgi, some in endosomes and lysosomes, little at PM

91
Q

seeing little inceptor at the PM means what?

A

it gets rapidly internalized

92
Q

they found that inceptor was internalized by what? how?

A

clathrin (found by colocalization, proximity ligation, mutants, chemical inhibitors)

93
Q

what is GM130?

A

cis-golgi network

94
Q

what is lysosome marker?

A

LAMP1 and LAMP2

95
Q

what did they find when studying inceptor interactions?

A

it binds strongly to INSR and IGF1R

96
Q

what did they find about insulin receptor internalization in lir-/- (inceptor ko) cells?

A

it decreases just a little

97
Q

what happened to INSR and IGF1R when they blocked inceptor internalization with an antibody?

A

increased INSR and IGFR at the surface

98
Q

remember: rapid internalization and recycling of INSR allows it to ?

A

always be able to be stimulated and to avoid desensitization

99
Q

conclusion of the paper?

A

inceptor is what allows B cells not to be overstimulated by the constant insulin as it is a stimulus of INSR and IGF1R internalization

ANAT365 (10 decks)

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