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Paper 2 > Human metabolism ALL > Flashcards

Human metabolism ALL Flashcards

1
Q

Insulin

A
  • A chain = 21aa, B chain - 30aa linked by 2 disulphide

- Preproinsulin → proinsulin

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2
Q

Metabolic effects of insulin

A
  • Fed state hormone
  • Obese subjects secrete ↑
  • T2D lose control over [glucose]
  • Major anabolic hormone, stimulates uptake of nutrients
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3
Q

Effects of insulin on carbohydrate metabolism

A
  • Effects:
    1. uptake of glucose in muscle + incorp into glycogen (GLUT4, GS, PDH)
    2. Inhibits hepatic production of glucose from glycogen breakdown + gluconeogenesis (stim of GS, inhib of glycogen phosphorylase + gluconeogenic E)
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4
Q

Effects on fat metabolism

A
  1. Stimulates synthesis of FA from glucose
  2. Uptake of TAG into adipose + inhibition of mobilisation of stored fat from adipose (stimulates extracellular lipoprotein lipases, inhibition of ATGL + HSL)
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5
Q

GS in muscle

A
  • GS (active) → GS-P (inactive)
  • Phosph at many sites by PKA, AMPK or GSK3
  • 3a,b,c,4,5 = GSK3
  • Insulin inhibits GSK3
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6
Q

Insulin receptor

A
  • Tetrameric
  • Insulin binds → relieves inhibition of tyrosine kinase activity → substrate recruited to IR → IRS1 is phosph + binds PI3K which catalyses PIP2 → PIP3 → PKB recruited + phosph
  • Phosph GSK3 at Ser21
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7
Q

GLUT4 in muscle + adipose

A
  • W/o insulin, 5% of GLUT4 = at cell surface

- Insulin promotes GLUT4 from GSV to cell surface by phosph 2 Rab GTPases (Rab13 in muscle)

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8
Q

PDH in muscle

A
  • PDH-P (inactive)
  • Activated by ↑ ratio of AcCoA : CoASH, NADH:NAD + ATP:ADP
  • Different isofordms
  • PDK4 phosph + inactivates PDH
  • Transcription of PDK4 = controlled by FOXO1, insulin → proteolysis + exclusion of FOXO1 → PDK4 x have TF → active PDH
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9
Q

HSL + adipose triacylglycerol lipase

A
  • TAG = surrounded by 100s of lipid droplet proteins
  • e.g. = perilipin (barrier btw lipase + substrate)
  • CGI-58 = activator for ATGL
  • FAB4 binds FA + transports from lipid droplet to plasma membrane
  • Adrenaline → PKA stimulated → perilipin fragments barrier, HSL recruited to surface of lipid droplet → CGI-58 binds ATGL → hydrolysis of TAG, FAB4 binds FA
  • Insulin ↓ cAMP, lipolysis inhibited
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10
Q

Transcriptional effects of insulin on hepatic gluconeogenic E

A
  1. FOXO1
    - insulin → PKB → Phosph FOXO1 → nuclear exclusion + degradation → x stimulate expression for G6Pase or PEPCK
  2. Creb
    - insulin → ↑ AKT which phosph Sik2
    - SIK2 phosph CBP + Crtc2 → Crtc2 degraded → inhibits transcription of gluconeogenic E
  3. PGC-1a
    - Inhibits recruitment to gluconeogenic E
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11
Q

Transcriptional effects of insulin on lipogenic gluconeogenic E

A
  • Insulin stimulates transcription of FA synthesis
  • All have TF SREBP which binds SRE
  • insulin ↑ SREBP-1c by ↑ its transcription and activation via RIP
  • RIP = when ER has ↓ cholesterol, SREBP2 moves from ER to Golgi by COPII, activated by Site1/2 protease → active TF, when ↑ cholesterol retained in ER
  • Insulin phosph SREBP1c, has ↑ affinity for SCAP, moves to Golgi + activated
  • Akt Phosphor + inactivates TSC1/2
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12
Q

Diabetes

A
  • Fasting hyperglycaemia + postprandial hyperglycaemia
  • T1D = defect in B cells of pancreas
  • T2D = insulin resistance, B cell secrete ↑
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13
Q

Changes to carbohydrate metabolism

A
  • Liver overproduces glucose from gluconeogenesis

- Muscle underutilises

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14
Q

Change to fat metabolism

A
  • Adipose overproduces FA as lipolysis x inhibited
  • ↑ FA stimulates oxidation in muscle, inhibits glucose ox through glucose-FA cycle
  • ↑ FA also stimulates ketone production
  • ↑ TAG, ↓ HDL
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15
Q

Insulin resistance

A
  • E intake > expenditure = surplus E stored as TAG in adipose
  • If x store more, TAG accumulate in muscle
  • PKCe sensitive to stimulation by DAG, recruited to membrane + phosph IR (imparts P13K/PKB)
  • But TAG accumulate not DAG
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16
Q

Paradox in liver metabolism

A
  • In diabetes, liver overproduces glucose
  • Explained by IR in gluconeogenesis
  • BUT glycogen breakdown x contribute
  • BUT liver produces VLDL TAG
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17
Q

Hypothesis : liver metabolism controlled by precursor supply

A
  • Gluconeogenesis = controlled by glycerol from adipose + aa from muscle
  • IR adipose overproduce glycerol + muscle aa
  • So can be explained (x involve liver IR)
  • TAG production = controlled by FA from adipose + esterification by glycerol-3-P made by IR adipose
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18
Q

Hypothesis: liver insulin resistance is selective x global

A
  • Insulin inhibits transcription of gluconeogenic E
  • In diabetes this = IR so transcription of key E x inhibited + glucose overproduced
  • Transcription of key E of FA + esterification stimulated by insulin which is overactive in IR
  • But x gives inside
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19
Q

Potential mechanism for IR

A
  • E intake > expenditure, E stored as TAG in adipose
  • When exceeded, ectopic fat causes IR
  • When B cells fail to compensate, abnormal carb metabolism results
  • In muscle = defective glucose uptake
  • In liver = glucose overproduced + TAGs by adipose
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20
Q

Glucagon

A
  • 160 aa precursor made in reaction by PC2
  • Hormone of starvation
  • After meal glucagon ↓
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21
Q

Glucagon target tissues

A
  • x glucagon receptor in human adipose or skeletal

- Lots in liver

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22
Q

Glucagon effect

Glycogen breakdown + glycogen synthesis

A
  • Target of PKA = phosphorylase kinase b + GS
  • GS phosph on site 2
  • Difference liver vs muscle = site 1a+b is only in muscle, 2 is in both
  • Protein phosphatase I has glycogen binding unit (G)
  • Gl lacks PKA phosph site
  • Phosphorylase a binds GL x Gm
  • Adrenaline → PKA → GM of PPI phosph → G + C disc → small inhibitor 1-P binds PPI + inactivates (x for GL)
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23
Q

Glucagon effect

Glycolysis + gluconeogenesis

A
  • Glycolytic E switched off, gluconeogenic on
  1. PFK + F1,6BPatase
    - F2,6BP = regulator, catalysed by bifunctional E
    - Glucagon → PKA → phosph bifunctional E on Ser32 → hydrolyses F2,6BP → glycolysis loses activator
  2. Pyruvate kinase (Liver)
    - Phosph by PKA (inactive)
    - Dephosph by PP1 (active)
    - Allosterically activated by F1,6BP, inactive by Ala (stimulates/inhibits phosphorylation)
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24
Q

Glucagon effect

Transcription

A

CREB

  • PKA → phosph CREB on Ser133 → translocates to nucleus
  • dephosph of CRTC2 → translocation to nucleus, forms complex
  • E.g. PEPC = ↑ glucagon, active PKA, CREB phosph, SIK2 phosph + x phosph CRTC2 so can bind CREB + CBP → transcription of gene
  • 2nd wave = PGC1a
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25
Q

Glucagon effect

FA synthesis + oxidation

A
  • Transport of FA to mit = mediated by CPT1/2, malonyl coA inhibits CPT1
  • Active ACC = FA + malonyl coA made, FA ox inhibited
  • Glucagon phosph + inhibits ACC in liver
  • AMPK phosph + inhibits ACC
  • 2 isofordms ACC2/ACC1
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26
Q

Liver metabolism branch points

A
  • Acetyl coA can be fed into TCA or HMG-coA cycle

- HMG coA synthase + citrate synthase compete for acetyl coA

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27
Q

Energy storage

A
  • TAG = most efficient way but need mechanisms for transport
  • Also glycogen, can make and degrade glycogen simultaneously
28
Q

Tissues w/o mitochondria

A
  • Glycolysis = entirely cytoplasmic
  • RBC entirely dependent on glucose as E source
  • Cori cycle (liver converts lactic acid back to glucose)
29
Q

Starvation in tissue w/ mitochondria

A
  • Range of fuels
  • Limited availability of body carb (only small amount of glycogen)
  • Best = fat
30
Q

Inhibition of glucose utilisation

A
  • Body glycogen used 24-48hr of starvation
  • FA replace glucose in muscle, ketone in brain
  • Blood brain barrier = impermeable to FA
31
Q

PDH

A
  • When active, pyruvate is committed to complete oxidation
  • Needs to be inhibited
  • PDH kinase phosph + inhibits PDH
32
Q

PFK

A
  • FA/ketone body ox ↑ which ↑ [citrate], inhibits PFK

- GLUT4 inhibited

33
Q

Ketone bodies as signals

A
  • Antilipolytic
  • Ketone bodies limit own precursor
  • Inhibit supply of glycerol
34
Q

Body protein in starvation

A
  • Indication = N excretion
  • As starvation proceeds, ↑ ammonia, ↓ urea excreted
  • Alanine + glutamine = most important aa
  • Sources of pyruvate for alanine (glucose, C skeletons, muscle glycogen)
  • Sources of pyruvate for glutamate (C skeleton form other aa)
35
Q

General

A
  • Fuel = blood glucose, muscle glycogen, blood FA, muscle TAGs
36
Q

Controlling metabolism by E status

A
  • AMP/ATP sensed + by AMPL
  • adenylate kinase amplifies small ↓ in [ATP] to ↑ in [AMP]
  • glycogen phosphorylase b = stimulated by ↑ AMP/ATP
  • PFK = regulated by ATP
  • Bypass hexokinase so 3ATPs made per glucose
37
Q

AMPK

A
  • GS + HMG Coa reductase are both phosph + inhibited by AMPK
  • ACC2 is phosph + inhibited
  • When AMP/ATP ↑, kinase active, ACC-P inhibited, x malonyl coA made, CPT-1 de-inhib, rate of FA ox ↑
38
Q

Controlling metabolism by nervous control

A
  • Mediated by Ca2+
  • Glycogen phosphorylase b (gamma subunit binds Ca2+, activates y subunit of phosphorylase b kinase which phosph + activates glycogen phosphorylase)
  • PDH (PDH phosphatase = stimulated by Ca2+, dephosph PDH → active form)
  • Isocitrate / a-ketoglut dehydrogenase
39
Q

Adrenaline

A
  1. glycogen breakdown in muscle + liver
    - adrenaline → cAMP → activates PKA → PKA phosph phosphorylase b kinase which phosph glycogen phosphorylase → ↑ G6P + ATP
    - PKA phosph + inhibits PP1
  2. TAG lipolysis in adipose
    - HSL phosph by PKA, ↑ activity
    - Perilipin 1 phosp by PKA → fragmentation of perilipin 1 barrier
40
Q

Types of muscle

A
  • Type 1 (aerobic, ↑ mit density, oxidative, slow)
  • SLOW = glucose → glycolysis → Krebs → Etc + can use FFA
  • Type IIa (int. of type I/IIb, slow contraction)
  • Type IIb (anaerobic, ↓ mit density, fast contraction)
  • FAST = glucose → glut4 → glycolysis → lactate
41
Q

Intracellular stores for exercise

A
  • e.g. creatine, glycogen, TAG
  • x need to mobilise
  • Limited, ↓ E dense
42
Q

Extracellular stores

A
  • e.g. blood glucose, FA
  • unlimited in size + ↑ E dense than glucose
  • But need to mobilise
43
Q

Muscle regulation during anaerobic exercise

A
  • More E from glycolysis w/ glycogen than glucose
  • In exercise, ↓ ATP, ↑ Pi, ↓ creatine phosphate
  • Glycogen phosphorylase = activated by Ppi
  • PFK regulated in parallel to glycogen breakdown
44
Q

Fatigue in anaerobic exercise

A
  • Lactic acid made to regenerate NAD+
  • ↓ pH → less Ca2+ released by sarcoplasmic reticulum
  • Inhibits PFK muscle
45
Q

Aerobic exercise

A
  • Type Ib muscle
  • Blood glucose = 4 min, liver glycogen = 18 min, muscle glycogen = 70 min
  • Adipose TAG → FA, 4018 mins
46
Q

Fatigue in aerobic exercise

A
  • Glycogen stores depleted
47
Q

Chlyomicron

A
  • Used to transport TAGS from diet to adipose (storage) or skeletal/cardiac for oxidation
48
Q

VLDL

A
  • Carry fat made from liver

- As transport TAG from liver to muscle/adipose, metabolised to IDL

49
Q

LDL

A
  • Transport cholesterol into body
50
Q

HDL

A
  • Carries cholesterol out of body
51
Q

Lipoprotein structure

A
  • Surface = phospholipid monolayer
  • Core = TAG, cholesterol esters
  • Chylomicron = largest + least dense, 99:1 lipid: protein, apolipoprotein B48, A1,2,C,E
  • VLDL 92:1, HDL 50:50
52
Q

Types of apolipoprotein

A
  • Non-exchangeble e.g. ApoB48 + ApoB100 (e.g. of mRNA editing)
  • All others = exchangeable
53
Q

LCAT

A
  • Activated by A1

- Converts free cholesterol to esterified cholesterol

54
Q

TAG transport

A
  • In starved state, body TAG mobilised as FA

- In fed, dietary TAG is transported to adipose for storage or skeletal/cardiac for oxidation

55
Q

Dietary fat → body fat

Exogenous pathway

A
  • Cholesterol is made by liver + enters circulation as a lipoprotein or is secreted into bile
  • TAGs x cross cell membrane intact, need to be hydrolysed + re-synthesised
  • Gastric lipases break TAG → DAG + MAG
  • Pancreatic lipases → monoacylglycerol + 2FA
  • Bile salts avoid product accumulation at interface
  • Bile salts removed w/ collapse
  • Glycerol phosphate pathway
56
Q

Re-synthesis of TAG

A
  • Newly made chylomicrons get exchangeable apoC11 + E from HDL in circulation
  • ER, PCTVs, Golgi
  • MTP
  • Smooth ER + RER, core expansion
57
Q

Lipoprotein lipase

A
  • Chylomicron arrives at adipose, needs to be hydrolysed
  • Completely hydrolyse TAG → FFA
  • Glycerol 3 phosphate pathway
  • Adipose x express glycerol kinase, get it from glycolysis via gly 3 P dehydrogenase
58
Q

Insulin + body fat

A
  • Insulin stimulates GLUT4 so glycolysis
  • This ↑ supply of glyc 3 p so FA esterification
  • Inhibits lipolysis by PKB phosph phosphodiesterase 3B, ↓ cAMP
  • Insulin stimulates transcription of lipoprotein lipase + FA synthesis E by activating SRBEP1c
59
Q

Endogenous pathway

A
  • Cholesterol made by liver + enters circulation
  • Dominant pathway for TAG synthesis in liver = glyc 3 phosph pathway + liver has glycerol kinase
  • VLDL released into circulation → acquires ApoCII + E → lipoprotein lipase makes IDL → LDL by ApoB100 addition → IDL taken up by liver
60
Q

Role of cholesterol

A
  • Regulates membrane fluidity

- Precursor for bile acids, vitamin D, steroid hormones

61
Q

Cellular cholesterol status

A

Sources of cellular cholesterol

  1. De novo synthesis
    (20-30 E, mevalonic A = 1st unique E, similar to ketone body synthesis, 2NADPH/H+, HMG coa reductase that response to [cholesterol]
  2. Circulating cholesterol carried by LDL
    - ↑ LDL receptor = ↑ capacity for uptake
    - Receptor mediated endocytosis, Cathrin coated pits, proton pump, pH optimum
62
Q

NPC1/2

A
  • NPC2 binds esterified cholesterol in lumen of ER + transfers to membrane bound NPC1
63
Q

Transcriptional regulation

A
  • LDL receptor + HMG CoA reductase have TF SREBP2
  • ER [cholesterol] ↑, SREBP2 binds INSIG + stays in ER
  • ” “ ↓ , SREBP2 goes to Golgi by COPII where activated by S1P/S2P, moves to nucleus
  • SCAP has sterol sensing domain + binds INSIG
  • ↑ cholesterol, SCAP binds cholesterol, x bind COPII, SCAP/SREBP retained in ER by INSIG
  • ↓ cholesterol, SCAP binds COPII, SCAP/SCREBP move to Golgi
64
Q

Endocytic cholesterol metabolism

A
  • Free cholesterol enters enterocyte via NPC1L1
  • Some cholesterol returns to lumen via ABCG5/8 in TICE
  • Remaining cholesterol is esterified by ACAT
65
Q

Cholesterol disposal

A
  • Excess cholesterol excreted
  • RCT, efflux of cholesterol on HDL to liver
  • In liver, secreted into bile, portion reabsorbed
66
Q

Cholesterol efflux from tissues

A
  • 4 pathways from a macrophage (2 need diffusion by SR-B1, 2 need ATP)
  • Liver + intestine make apoA1
  • ApoA1 gathers cholesterol from 2 diffusion pathways
  • As ApoA1 gets cholesterol, matures to HDL + LCAT
67
Q

Good vs bad cholesterol

A
  • Were cholesterol reaches
  • Cellular cholesterol is safe
  • Most carried by LDL (bad), minority by HDL (good)
  • If endothelial layer damaged, LDL taken up into sub-endothelial space + oxidised (bad)
  • Statins inhibit HMG CoA reductase
  • ↑ LDL receptor no. → ↑ capacity for cholesterol uptake, ↓ circulating LDL
  • Epidemiological studies

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