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Gastrointestinal System > Self Study: Fatty Acid Metabolism - Abali > Flashcards

Self Study: Fatty Acid Metabolism - Abali Flashcards

1
Q

fatty acid structure

A
  • hydrocarbon chain with terminal carboxylyl group (-COOH, ionized at pH 7)
  • bonds determine saturation
    • all single bonds = saturated
    • 1 or more double bonds = unsaturated (usually cis)
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2
Q

essential fatty acids

  • why “essential”
  • type (omega…)
  • fx
  • sources
A

WHY ESSENTIAL?

mammals can’t introduce double bonds beyond C9, so can’t make either one

linoleic acid 18:2(9,12)

  • omega 6
  • pro-inflammatory

linolenic acid 18:3(9,12,15)

  • omega 3
  • anti-inflammatory

arachidonate acid 20:4(5,8,11,14)

  • omega 6
  • synth’d from linolenic
  • prostaglandin precursor

sources: SMASH (salmon, mackerel, albacore, sardines, halibut)

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3
Q

fatty acid synthesis : role of the citrate shuttle

A

FA synthesis takes place in cytosol of liver and adipose cells

problem: main ingredient (acetyl CoA, from glycolysis or alcohol metab) is in the mito matrix, and the inner mito membrane is v selective

solution: citrate shuttle!

  • in mito matrix: acetyl CoA + OAA → citrate [citrate synthase]
  • transport across inner membrane via citrate shuttle
  • in cytosol: citrate → acetyl CoA + OAA [ATP-citrate lyase]

summary: citrate shuttle allows for acetyl CoA to get from mito matrix (where it’s synthesized) to cytosol (where it’s needed for FA synthesis)

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4
Q

fatty acid synthesis: malonyl CoA formation

  • enzyme/cofactor
  • regulation of enzyme
A

acetyl CoA → malonyl CoA [acetyl CoA carboxylase; biotin cofactor]

COMMITTED RXN

acetyl CoA carboxylase is an ABC carboxylase

  • ATP (plenty in fed state), biotin required
  • dimer when inactive, polymer when active

allosteric regulation

+ : citrate

  • : long chain fatty acyl CoA

hormonal regulation

+ : insulin [dephos via protein phosphatase]

  • : glucagon, epi [phos via AMP-dep kinase]
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5
Q

fatty acid synthesis: palmitate formation

A

chain elongation via fatty acid synthase, eventual synth of palmitate

  • multi-enzyme complex : condensation, reduction, dehydration, reduction activity
    • 2 reductions = 2 NADPH consumed as chain extended by 2 Cs
    • also need pantothenic acid/B5 for fatty acid synthase

final pdt: 16C palmitate/palmitoyl CoA/palmitic acid

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6
Q

fatty acid synthesis: fates of palmitate

A

can be either…

elongated (mitochondria, ER)

  • 2 C elongation
  • stearate 18:0 is most common pdt

desaturated (ER)

  • via fatty acyl CoA desaturase, using NADPH as reducing agent
    • reduces bond b/w C9 and C10
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7
Q

summary: FA synthesis

A

acetyl CoA [transported from mito matrix to cytosol via citrate shuttle]

→ malonyl CoA [via acetyl CoA carboxylase; requires ATP, biotin]

→ palmitate [via fatty acid synthase; requires NADPH]

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8
Q

fatty acid synthesis: diabetics

A

lack of insulin or insulin-resistance means no activation of acetyl CoA carboxylase

[insulin also upregs malonyl CoA → palmitate]

can’t turn acetyl CoA → malonyl CoA!

  • diminished FA synth
  • acetyl CoA → ketone body production
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9
Q

what happens to FAs in healthy individuals?

A

triacylglycerol synthesis

TAG : glycerol + 3 FAs (can be diff lengths, sat)

  • need glycerol phosphate, derived from DHAP made in glycolysis
  • need FAs made in liver, adipose tissue

steps of synthesis:

  1. DHAP → glycerol 3 P [glycerol3P DH]
  2. esterification rxns
  3. addition of acyl groups to glycerol backbone [3 acyltransferases]
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10
Q

sites of TAG synthesis

  • 2 pathways of TAG synthesis
A

liver is main site of TAG synthesis

adipose tissue also contributes

2 pathways of TAG synthesis boil down to two ways to make glycerol3P

1. glycolysis intermeds: glucose → DHAP → glycerol3P [glycerolP DH]

  • liver
  • adipose tissue (regulated by glucose availability, mediated by GLUT4, which is insulin dep - no glucose, no insulin → no glycerol3P, no TAG synth in adipose tissue]

2. free glycerol → glycerol3P [glycerol kinase}

  • liver only
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11
Q

sites of TAG storage

  • role of glycerol phosphate
A

only adipose tissue can store TAGs

  • most TAG synth happens in liver → packaged and shipped into circ in VLDLs → TAGs degraded into glycerol and FAs by endothelial cell lipoprotein lipase (LPL)
  • adipose tissue picks up FAs, does not pick up glycerol (bc it doesn’t have glycerol kinase)
    • FAs packaged back into TAGs in adipose cells
  • glycerol that was not picked up heads back to liver and is re-P’d by glycerol kinase to recycle into TAG synth
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12
Q

regulation of TAG synthesis

A

fed state: insulin upregs glycolysis and LPL

  • glycolysis: accumulation of acetyl CoA and glycerol3P
    • acetyl CoA → FAs : FAs + glycerol3P → TAGs
  • LPL: efficient release/uptake of free FAs by adipose tissue

alcohol : impairs VLDL secretion

  • alcoholic fatty liver disease!
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13
Q

mobilization of stored fat

A

adipose tissue

+ : stress hormones (glucagon, epi, cortisol) trigger hormone-sensitive lipase : TAG → glycerol + FAs, both released into bloodstream

liver

+ : glucagon, cortisol upregulate…

  • gluconeogenesis
  • beta ox FA degradation
  • ketogenesis → can’t be used by liver! transported out for use by extrahep tissues
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14
Q

mobilization of TAGs in adipose tissue : role of perilipins

A

TAGs are coated with perilipins (protein fam)

fx in regulation of basal and hormonally stimulated lipolysis

  • basal: restricts access of cytosolic lipases to TAGs → promotes TAG storage
  • energy deficit/hormone stimulation: perilipin P’d by PKA → facilitates max lipolysis via HSL (hormone sensitive lipase) and ATGL (adipose triglyceride lipase)
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15
Q

beta oxidation : basics

A

each cyle of beta ox generates…

  • 1 FADH2
  • 1 NADH
  • 1 acetyl CoA

FAs arrive in cytosol after mobilization from adipose tissue, but have to be transported into mitochondria for beta ox

  • carnitine cycle : used for FAs 14C or longer
  • carnitine has affinity for activated FAs (over free FAs) - CoA is the activating molecule in this case
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16
Q

carnitine shuttle : components

A

carnitine shuttle = CPT (carnitine palmitoyltransferase) = CAT (carnitine acyl transferase) is composed of two enzymes:

1. CPT I = CAT I : outer part of inner mito mem

fatty acyl CoA + carnitine → fatty acyl carnitine + free CoA

  • fatty acyl carnitine moves into mito matrix through shuttle; CoA hangs out in cytosol
  • inhibition: malonyl CoA (int of FA synth) inhibits CPT I → prevents synth/degrad cycling

2. CPT II = CAT II : inner part of inner mito mem

fatty acyl carnitine + CoA → fatty acyl CoA + free carnitine

  • CoA is already present in mito matrix; freed carnitine moves out into cytosol via shuttle
  • fatty acyl CoA moves on into beta oxidation
17
Q

carnitine shuttle : mech of action

A

summary/point: need some way to get FAs into mitochondria for beta ox. carnitine shuttle will do the job, but only if FAs are “activated” by CoA [accomplished by fatty acyl CoA synthetase in cytosol]

problem here: CoA can’t get through the inner mito mem

solution: CPT I/CPT II system that strips CoA/adds carnitine and vice versa

outcome: fatty acyl CoA moved into mito matrix, where beta ox can take place

18
Q

carnitine shuttle nomenclature reminder

CPT I & II = CAT I & II

carnitine palmitoyl transferase = carnitine acyl transferase

CAT = CACT

carnitine acylcarnitine transferase

A
19
Q

beta oxidation : overview

A

series of rxns involving C3 (beta C), shortens FA chain by 2Cs

each set of rxns produces: 1 NADH, 1 FADH2, acetyl CoA (for TCA cycle) + shortened FA chain

each involves: oxidation, hydration, oxidation, 2C cleavage

  • catalyzed by acyl CoA dehydrogenases (diff DHs for diff length chains: short, med, long, v long chain acyl CoA dehydrogenases)
20
Q

beta oxidation compared to other metab

  • energy yield
A

beta oxidation of palmityl CoA (16C) yields…

  • 7 FADH2 = 14 ATP
  • 7 NADH = 21 ATP
  • 8 acetyl CoA x TCA cycle = 96 ATP

131 ATP

takeaway: beta ox >>> glycolysis

21
Q

what if a FA is not a long chain FA?

alternative oxidation pathways for…

  • unsaturated FAs
  • branched chain FAs
  • medium and short chain FAs
A

unsaturated FAs

  • yield less FADH2 than saturated FAs
    • already partially oxidized, so fewer ox rxns overall
  • need addtl enzymes to process

branched chain FAs

  • alpha ox → acetyl CoA, propionyl CoA
  • clinical: defect in alpha ox can lead to nerve tissue deposits of phytanic acid (branched chain lipids in plant chlorophylls)

medium/short chain FAs

  • can get into mito matrix without carnitine shuttle
  • need specific DHs for beta ox
22
Q

oxidation of FAs with odd numbers of C

A

beta ox of odd-numbered FAs goes on until you end up with a final 3C FA

  • yields acetyl CoA, NADH, FADH2, and a propionyl CoA

propionyl CoA (3C) → methylmalonyl CoA (4C) [propionyl CoA carboxylase; ABC carboxylase]

methylmalonyl CoA → succinyl CoA [methylmalonyl CoA mutase; requires B12*** - links to signs of B12 def]

succinyl CoA → energy via TCA cycle or shuttled into gluconeogenesis!

  • only odd chain FAs are glucuneogenic!
23
Q

B12 deficiency and methylmalonyl CoA

  • identifying B12 def
  • explaining symptoms of B12 def
A

conversion of methylmalonyl CoA → succinyl CoA requires B12 (and only B12; not B9)

  • B12 def → methylmalonic acid buildup!
  • can be used to distinguish B12 def from folate def

methylmalonyl CoA is analogous to malonyl CoA (made in committed step of FA synth)

  • in B12 def, built up methylmalonic acid begins subbing in for malonyl CoA → branched chain FAs
  • if integrated into membranes of nervous tissue, interferes with tissue integrity : neuropathy!
24
Q

carnitine shuttle defects

A

pathophysio

  • 1: congenital CAT I deficiency
  • 2: low dietary intake of carnitine

symptoms

  • muscle pain/fatigue following exercise (inability to utilize FAs for energy after glycogen stores depleted)
  • high FA conc in blood (inability to utilize, so mobilized FAs stay in blood)
  • hypoketotic hypoglycemia (cant produce ketone bodies without FA metab!)

tx

  • high carb diet supplemented with medium and short chain FAs
25
Q

CAT I/CPT I deficiency

A
  • relatively rare
  • affects primarily liver
  • leads to reduced FA oxidation and ketogenesis

symptoms

  • most common: hypoketotic hypoglycemia
  • elevation in blood carnitine
  • hepatomegaly (liver), weakness (muscles)
26
Q

CAT II/CPT II deficiency

A

3 main forms

1. adult myopathic form : muscle pain, fatigue, myoglobinuria after exercise

2. severe infantile multisystem form : first 6-24 months of life

  • hypoketotic hypoglycemia → severe hepatomegaly, cardiomyopathy

3. neonatal lethal form : rarest, sx hrs-4d after birth

  • resp failure, hepatomegaly, seizures, hypoglycemia, cardiomegaly → fatal arrythmia
27
Q

impaired medium chain FA oxidation

A

MCAD (medium chain acyl CoA DH) deficiency due to auto recessive disease, presents in infancy

characteristic symptom: hypoketotic hypoglycemia

diagnosis:

  • plasma/urine buildup of MC carboxylic acids, acyl carnitines, dicarboxylic acids due to omega ox
  • possible hyperammonemia due to liver damage

tx : frequent feeding, avoiding fasting, carnitine supplementation

28
Q

methylmalonyl CoA mutase deficiency

A

key enzyme in processing odd-number FAs

could present as a result of…

  • B12 def
  • IF def
  • actual enzyme def (rarer than other causes)

results in methylmalonyl aciduria → peripheral neuropathy

tx: B12 supplementation

29
Q

when and why does ketone body synthesis happen?

A

in fed state, production of ketone bodies is low

in fasted state, low blood sugar → more beta ox → more acetyl CoA

  • acetyl CoA buildup in fasted and starvation state exceed capacity of TCA cycle → utilized in ketogenesis in mito
  • heart and sk muscles use ketone bodies for energy; saves glucose for the brain
30
Q

ketone synthesis vs chol synthesis

A

v similar to chol synthesis…to a point

site of synthesis

  • ketones : mito
  • chol : cytosol, ER

key enzyme

  • ketones: HMG CoA lyase
  • chol: HMG CoA reductase
31
Q

ketone synthesis: major keys

  • key enzymes
  • major ketone products
A

occurs primarily in liver

makes use of mito isoform of HMG CoA synthase

  • only found in liver, regulated at transc level
      • : fasting, cAMP, FAs
      • : feeding, insulin

HMG CoA then cleaved by HMG CoA lyase → acetoacetate, which can be modified into DBhydroxybutyrate, acetone*

32
Q

ketone bodies as alt fuel

A

HBhydroxybutyrate → acetoacetate → energy production

*acetone can’t be converted back to acetoacetate; excreted via expiration due to volatility

pathway

acetoacetate → acetoacetyl CoA [CoA transferase/thiphorase*]

  • CoA is donated from succinyl CoA

acetoacetyl CoA → 2 acetyl CoA [thiolase]

  • acetyl CoA heads into TCA cycle!

*CoA transferase NOT present in liver. why?

  • don’t want liver to use it’s own supply as fuel! makes more available to others (brain)
33
Q

why ketones and not FAs for brain food?

A

FAs are bound to albumin in plasma : cant cross the blood/brain barrier!

ketones are like transportable equivalents of FAs

34
Q

regulation of ketone body synth

A

blood glucose and availability of acetyl CoA dictate ketone body synth

fed state: glucose is broken down via glycolysis, TCA cycle, oxphos; excess is moved into glycogen, HMP, and FA synth

fasting/starvation: different story : no glucose!

  • absence of carbs during fasting starvation leads to FA breakdown and buildup of acetyl CoA
    • can’t shuttle to TCA cycle bc intermediates (like OAA) will already be tapped for gluconeogenesis
35
Q

role of OAA in determining whether ketone synthesis happens

A

acetyl CoA only enters TCA cycle if OAA is available for formation of citrate

when you’re low on carbs, body shuttles OAA into gluconeogenesis

  • carb starvation is required before you’ll take the acetyl CoA (that you now CANT combine with OAA to enter TCA cycle) and pump it into ketone synth
36
Q

plasma concentration as fast occurs

A

FAs increase approx 3-4 hr post-meal, increase up to 2-3 d of fast

in liver, ketone synth rises with supply of FAs

in blood, ketones rise and continue to rise (prob bc utilization by sk muscle drops)

  • after 2-3 d starvation, blood ketone reaches level that allows them to enter brain cells → use as fuel (up to 2/3 of brain egy supply in prolonged fast) reduces brain’s glucose req
  • reduction in glucose req spares sk muscle, which is major source of a.a. precursors for gluconeogenesis!
37
Q

ketone bodies and DKA

A

insulin deficiency/insensitivity (diabetes) leads to drop in cellular glucose levels

  • inability to replenish TCA cycle ints (esp OAA)
  • limits ability of mobilized FAs to be utilized by cells through TCA cycle
    • acetyl CoA from FA metabolism is shunted into ketogenesis instead

accumulation of ketone bodies → low blood pH → DKA and pathology

Gastrointestinal System (35 decks)

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