Lipid Metabolism Flashcards

1
Q

Function of Lipids

A

Fuel stores (provide energy), structural components (plasma membranes), signaling molecules (signal transduction pathways), other (insulation, generating heat, fat digestion)

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2
Q

Fatty acid synthesis

A
  • occurs primarily in the liver
  • requires coordination between cytosolic and mitochondrial reactions
  • the precursor is Acetyl CoA
  • Three phases
  • methyl and carboxyl ends
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3
Q

Phase 1 Fatty acid synthesis

A

cytosolic entry of acetyl CoA (from mitochondria)

    1. oxaloacetyate + acetyl CoA –> Citrate (via citrate synthase)
      1. citrate transported from mitochondria to cytosol, then citrate lyase –> OAA + Acetyl coA
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4
Q

Rate limiting enzyme fatty acid synthesis

A
Acetyl CoA carboxylase
carboxylates acetyl CoA --> Malonyl CoA
- upreg by insulin, citrate
- downreg by glucagon, epinephrine, high AMP, palmitate, PUFA
- This is phase 2 FA synthesis
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5
Q

Phase 3 fatty acid synthesis

A

FA synthase catalyzes 7 reactions malonyl CoA + Acetyl CoA ——> palmitate

  • FA synthase = 7 enzymes and carrier protein
  • Condensation, reduction, deydration, reduction for each of the 7 reactions
  • upreg by phos sugars, glucocorticoid hormones, high carb/low fat diet, insulin
  • down reg by high fat diet (starvation), PUFAS
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6
Q

Synthesis of TAG in intestinal cells

A
  • promoted by dietary TAG - broken down into MAG + Free FA in intestinal lume, separately transported into intestinal cell
    2. Fatty acyl coA synthase turns FA into Fatty acyl CoA (ATP –> AMP)
    3. MAG + Fatty acyl CoA –> Diacyl Glycerol (DAG)
    4. DAG acyl transferase + DAG –> TAG in intestinal cell, with side products apolipoproteins and other lipids.
    5. TAGs packaged into chylomicrons and put into bloodstream
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7
Q

Synthesis of TAGs in Liver

A
  • Promoted by excess carbs
    1. glucose + glycerol –> Glycerol-3-Phos (G-3-P)
    2. G-3-P backbone for TAG synthesis
    FFA (synthesized in liver from acetyl coA) added to G-3-P to form TAGS
    3. TAGs packed w/ apolipoproteins and other lipids –> VLDL, released to bloodstream as VLDL
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8
Q

Synthesis of TAGs in Adipocytes

A
  • promoted by excess carbohydrates and fats
    1. glucose + glycerol –> Glycerol-3-Phos (G-3-P)
    2. G-3-P backbone for TAG synthesis
    3. FFA obtained from breakdown of chylomicrons and VLDL in blood, by action of capillary lipoprotein lipase
    4. G-3-P and FFA form TAGS, then stored in adipocytes
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9
Q

Synthesis of longer chain fatty acids

A

Elongation - palmitate converted to longer chain FA in smooth ER or mitochondria
- uses NADPH as reducing power
in SER - Malonyl CoA as C donor
in mitochon. - uses Acetyl CoA as donor

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10
Q

Desaturation/unsaturation

A

Occurs in smooth ER, uses NADPH and O2, catalyzed by Acetyl coA denaturases (4 different types in humans - 4, 5, 6, 9)

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11
Q

Linoleic acid

A

omega 6 fatty acid

- used to make arachidonic acid (precursor for eicosanoids)

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12
Q

Linolenic acid

A

omega 3 fatty acid

- used to make icosapentanoic acid (EPA) and DHA (docosahexanoic acid)

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13
Q

TAG breakdown

A

4 major lipases used: ATGL, HSL, LPL, MAG lipase
- stimulated by hunger and exercise
- glucagon and epinephrine bind to GPCR (Gs), activates adenylate cyclase –> activates cAMP –> PKA
- PKA phosphorylates HSL
- PKA also phos perilipin –> phos ATGL,
TAG –> DAG –> MAG –(MAG lipiase)–> FA + glycerol

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14
Q

Perilipin

A

proteins that coat lipid droplets in adipocytes and muscle cells
- regulate lipolysis by controlling physical access to HSL (block them from doing their job to TAG)
(phosphorylation of perilipin allows for association between HSL and TAG)
- overexpression inhibits lypolysis, knockout causes easy lipolysis

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15
Q

Catabolization of Fatty acids (phase 1)

A

Occurs in cytosol (process of transfering FA to mit.matrix. Need to be activated

  • Fatty acid crosses into cytosol from adipocyte
  • fatty acyl coA synthetase (+ATP) makes Fatty acyl coA so it can cross through outer mitochond. membrane
  • Carnitine palmitoyltransferase-1 (rate limiting step) transfers Fatty Acyl from FA-CoA to carinitine –> forms FA carnitine.
  • carnitine acylcarnitine translocase - antiporter (FA-Carnitine in and carnitine out) in intermembrane space
  • carnitine palmitoyl transferase II - located in inner mitochondrial membrane, transfers fatty acyl from FA-carnitine to CoA, forms FA-CoA
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16
Q

Catabolization of Fatty acids (phase 2)

A

occurs in mitochondiral matrix, B oxidation of FA (saturated, even #C, 16-20C). Decreases by 2C each cycle
- four main steps, makes energy rich molecules.
1. Oxidation (done by ACAD, acyl coA dehydrogenase) (+2 ATP)
2. Hydration
3. Oxidation (+3 ATP)
4. Thiolysis (+12 ATP)
total of ~129 ATP

17
Q

After FA breakdown, products:

A
  • Acetyl coA enters TCA cycle –> NADH
  • FADH2 delivers e- to CoQ/ubiquinone –> ATP
  • NADH delivers e- to complex 1 of ETC –> ATP
18
Q

Breakdown of odd-chain fatty acids

A

steps are the same until chain is down to 3C

  • propionyl CoA carboxylase adds a C to make 4C chain (methylmalonyl CoA)
  • then succinyl CoA –> TCA cycle for energy production
19
Q

Unsaturated fatty acid breakdown

A
  • enzymes (ACADS) fail when they reach double bonds
  • steps are the same until double bond, then
    reductase reduces double bond,
    isomerase moves disruptive double bond
20
Q

Long chain fatty acid breakdown

A

longer than 20C, done in peroxisome

  • B oxidation in peroxisomees does not generate ATP
  • forms FADH2 –> H2O2 –> catalase converts H2O2 into water and oxygen.
  • when FA becomes ~20C then it is shipped to mitochondria for regular breakdown
21
Q

MCAD deficiency

A

(MCAD activates medium chain fatty acid breakdown)
- deficiency = impaired breakdown
~C8, if not broken down they accumulate in the liver and become toxic
- interferes with urea, elevated levels of ammonia
- leads to secondary carnitine deficiency
- depend on glucose for energy source

22
Q

Ketone bodies

A

made when fasting and no glucose available
- fatty acids break down to Acetyl CoA, then break down
- water soluble and ACIDIC
Acetyl CoA + Acetyl CoA –> Acetoacetyl coA –> HMG CoA –> Acetoacetate (then makes acetone and Bhydroxybutyrate)
Liver secretes them to the bloodstream and they are picked up by tissues
all ketone bodies formed back to acetoacetate (makes NADH), forms 2X Acetyl CoA –> TCA cycle, –> energy

23
Q

Ketoacidosis

A

physiological - mild to moderate increase in ketone bodies, uses for energy (OK)
pathological - when glucose/insulin ratio is inceased, carb metabolism impaired, favors FA breakdown.
- increased gluconeogenesis, reduced oxaloacetate –> stops citric acid cycle. increased ketone bodies in blood causes acidic blood pH

24
Q

3 ketone bodies

A

(made in the liver)
acetone
betahydroxybutyrate
acetoacetate