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SFM > (L5) Lipid Metabolism > Flashcards

(L5) Lipid Metabolism Flashcards

1
Q

What is the major source for fatty acid synthesis?

L5 S6 LO1

A

Dietary carbohydrates

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3
Q

In what tissues do fatty acid synthesis occur?

L5 S7 LO1

A
  • liver (primary)
  • adipose tissue
  • brain
  • kidney
  • lactating mammary glands
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4
Q

What is the precursor of fatty acid synthesis?

L5 S8 LO1

A

Acetyl-CoA

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5
Q

What steps are involved in transport of mitochondrial acetyl CoA to the cytoplasm?

L5 S12-13 LO1

A
  • condensation with oxaloacetate to for citrate (via citrate synthase)
  • transport of citrate from mitochondria
  • conversion back to acetyl CoA (via ATP citrate lyase)
  • oxaloacetate reduce to malate (via malate dehydrogenase)
  • oxaloacetate transported back into the mitochondria via malate-α ketoglutarate transporter and oxidized back to oxaloacetate (via malate dehydrogenase)
  • *or**
  • malate converted to pyruvate in cytoplasm (via malic enzyme) then transported into mitochondria
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6
Q

What are the major steps of fatty acid synthesis?

L5 S9 LO1

A
  • movement of mitochondrial acetyl CoA to the cytoplasm
  • generation of malonyl CoA (carboxylation)
  • fatty acid chain formation
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7
Q

What are the regulators of citrate lyase?

L5 S11 LO2

A

Activators:

  • glucose
  • insulin

Inhibitors:

  • PUFA
  • leptin
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8
Q

What are the regulators of acetyl CoA carboxylase?

L5 S14 LO2

A

Activators:

  • citrate
  • insulin (dephosporylates it)

Inhibitors:

  • glucagon (phos)
  • epinephrine (phos)
  • AMP (Amp kinase)
  • palmitate
  • PUFA
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9
Q

What is the function of acetyl CoA carboxylase?
What special features does it have?

L5 S15 LO1

A

Carboxylates acetyl CoA (2 carbons) using CO2 to form malonyl CoA (3 carbons).

Uses ATP for bond energy.

Uses biotin as cofactor.

**rate limiting step

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10
Q

What are the regulator of the fatty acid synthase complex?

L5 S17 LO2

A

Activators:

  • insulin
  • glucocorticoid hormones
  • High carb/low fat diets increase synthesis.

Inhibitors:

  • PUFA
  • high fat diets and starvation
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11
Q

What is the function of fatty acid synthase complex?
What special features does it have?

L5 S19;21 LO1

A

In seven reactions it takes 7 malonyl CoA, 1 acetyl CoA, and 14 NADPH to form palmitate (16C).

Complex formed of two identical dimers that have 7 catalytic activities and an acyl carrier protein (ACP).

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12
Q

What is the total equation for the reactions catalyze by fatty acid synthase?

L5 S21 LO1

A

Reactants:

  • 1 acetyl CoA
  • 7 malonyl CoA
  • 14 NADPH
  • 14 H+

Products:

  • palmitate
  • 14 NADP+
  • 8 CoA
  • 6 H2O
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13
Q

What are the reactions catalyzed by fatty acid synthase?

L5 S22 LO1

A
  • condensation
  • reduction
  • dehydration
  • reduction
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14
Q

What are the main sources of NAPDH?

L5 S23 LO1

A
  • pentose phosphate pathway

- malic enzyme

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15
Q

How and where are fatty acids longer than palmitate (C16) generated?

L5 S32 LO3

A

Location:

  • smooth ER (uses malonyl CoA)
  • mitochondria (uses acetyl CoA)

Synthesized by addition of 2 carbon groups.

NADPH used as reducing agent.

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16
Q

How and where are unsaturated fatty acids generated or obtained from?

L5 S33 LO3

A

Catalyzed by acyl CoA desaturases in the SER

4 variaties of desaturaes:

  • Δ4 (between carbon 4-5)
  • Δ5 (between carbon 5-6)
  • Δ6 (between carbon 6-7)
  • Δ9 (between carbon 9-10)

Use NADH/NADPH as reducing agent

Fatty acids with double bonds beyond carbon 9-10 (omega 3 and 6 FAs) cannot be synthesized by humans and must be ingested

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17
Q

What are the essential fatty acids and what are they used to synthesize?

L3 S34 LO3

A 
Linoleic acid (18:2 ω6)
-arachidonic acid (20:4 ω6)

Linolenic acid (18:3 ω3)

  • EPA (20:5 ω3)
  • DHA (22:6 ω3)
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18
Q

What introduces double bonds in FAs and where can double bonds be introduced in humans?

What is significant about where humans can introduce double bonds?

L5 S33 LO3

A

Desaturates introduce double bonds

Double bonds can be introduced at:

  • 4-5
  • 5-6
  • 6-7
  • 9-10

Since double bonds cannot be introduced beyond the 9th carbon, ω3 and ω6 fatty acids cannot be made.

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19
Q

Phase 1 FA synthesis

A
  • Step 1- Condensation of Acetyl CoA with oxaloacetate (OAA) to form citrate. Catalyzed by citrate synthase
  • Step 2 – Transport of citrate from mitochondria to cytosol. Via a citrate transporter
  • Step 3 – Citrate converted back to Acetyl CoA and OAA. Catalyzed by citrate lyase
  • Acetyl CoA used for FA synthesis in cytoplasm (uses ATP which is hydrolyzed to ADP + Pi)
  • Step 4 – OAA reduced to malate by malate dehydrogenase and then malate to pyruvate via malic enzyme
  • Step 5- Malate transported into mitochondria via malate-α ketoglutarate transporter and oxidized to OAA by malate dehydrogenase.
  • Step 6- Cytosolic malate converted to pyruvate by malic enzyme. Pyruvate transported to mitochondria via pyruvate transporter and carboxylated to OAA by pyruvate carboxylase.
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20
Q

What does malonyl CoA inhibit?

A

Carnitine acyltransferase I (CPT 1)

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21
Q

Fatty Acid Synthase Complex

A
  • Large multi-enzyme complex.
  • Composed of 2 identical dimers (260 kDa each).
  • Two dimers arranged in head to tail conformation
  • Each has 7 enzyme activities and an acyl carrier protein (ACP).

It makes palmitate (16:0)

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22
Q

Reaction catalyzed by FAS

A

1) acetyl group binds on the cystine-sh residue and the manonyl group binds to the Pan-SH group
- then a condensation reaction occurs

2) then the beto keto acyl group is reduced and NADPH is oxidized
3) then a dehydration reaction occurs
4) then a reduction reaction occurs (NADPH is ox again) and then the 4 chain fatty acyl group is then attached to the cystine group again and 6 more cycles occur until palmitate is formed and the product is relased.

23
Q

Elongation of FA

A
  • •Elongation – Palmitate converted to longer chain fatty acid in smooth endoplasmic reticulum (SER) or mitochondria
  • •Brain cells need longer chain fatty acids (C18- C24)
  • FA lengthened 2 carbons at a time
  • NADPH is used as reducing power
  • SER pathway uses Malonyl CoA as carbon donor
  • Mitochondria uses Acetyl CoA as carbon donor
24
Q

Essential Fatty Acids

A

•Need to ingest these via diet or their precursors such as:

  • Linoleic acid (18:2 ω6)
  • Linolenic acid (18:3 ω3)
25
Q

Linoleic acid is used to make___________

A

arachidonic acid (20:4 ω6)

-(precursor for eicosanoids)

26
Q

Regulation of Fatty acid synthase (FAS)

A

-insulin and glucocorticoid hormones increase synthesis
-high carb/ low fat increase synthesis
-high fat and starvation lowers synthesis
PUFA supresses synthesis

27
Q

Where does TAG synthesis occur?

A

denovo tag synthesis occurs in:

Adipocytes and Hepatocytes

28
Q

Linolenic acid is used to make

A

-eicosapentanoic acid (EPA) (20:5 ω3) and -docosahexanoic acid (DHA) (22:6 ω3)

29
Q

TAG Synthesis in Intestinal Cells

A
  • Dietary TAGs broken down to Monoacylglycerol (MAG) and FFA in intestinal lumen by pancreatic lipases
  • Intestinal cells resynthesize TAGs using MAG as backbone and adding 2 FFAs.
  • TAGs packaged with apolipoproteins and other lipids (phospholipids, cholesterol, fat soluble vitamins) to form a lipoprotein called chylomicron.
  • Chylomicrons are released into the lymphatic system and enter blood via thoracic duct
  • TAG synthesis in intestinal cells promoted by dietary TAGs
30
Q

What does fatty acyl coa synthase do?

A

FA ACTIVATION

WHEN FA are broken down and digested they must be activated before they can be attached to a backbone again. They are activated by FATY ACYL COA synthase.

31
Q

TAG synthesis in liver

A

This synthesis is DENOVO

  • Acetyl COA is turned into FA
  • FA are activated
  • Glycerol 3 phosphate is made and the activated FA are attached
  • TAGs packaged with apolipoproteins and other lipids (phospholipids) to form a lipoprotein called Very Low Density Lipoproteins (VLDL)
  • VLDL released into bloodstream
  • TAG synthesis in hepatocytes promoted by excess carbohydrates
32
Q

TAG synthesis in adipocytes

A
  • Glucose forms G-3-P
  • G-3-P used as backbone for TAG synthesis
  • FFA (obtained from breakdown of chylomicrons and VLDL in blood) by the action of capillary lipoprotein lipase
  • G-3-P and FFA form TAGs
  • TAGs stored in Adipocytes
  • TAG synthesis in adipocytes promoted by excess carbohydrates and fats

-you have an enzyme called capillary lipoprotein lipase which is activated by insulin which allows TAG break down so they can be digested by FA for tag synth

33
Q

Breakdown of TAGs

A

1) hormone sensitive lipase acts on FA (stimulated by glucagon, epi and norep, ihibited by insulin) which releases a FA

TAG -> DAG

2) then lipoprotien lipase will make
DAG –> MAG

3) then monoacylglycerol lipase (MAG lipase) will make FA + glycerol

FA are then released in the blood to go where ever they need to
-short chain < 6C are soluble
greater than that you need albumin so it wont stick to blood vessels

34
Q

What happens after FA release?

A

What happens after FA release?
1) IF YOU are resting yet still hungry liver can break it down to release energy

2) If you are excercing: muscles can use FA to give body energy

35
Q

HSL Regulation

A

-Modulated by phosphorylation

Major controllers of the signaling are: (phos)

–Glucagon (secreted in response to hunger)

–Epinephrine/ norep (secreted in response to exercise)

Fed status signal inhibits mobilization of TAGs:

–Insulin (secreted in response to a high carb meal)

Dephosphorylates HSL (via activation of protein phosphatase I) to inhibit lipolysis

36
Q

Regulation Mobilization of Fatty Acids from Adipocytes with ATGL

A

Activate lipoysis:

1) glycagon and or epi will bind to a receptor
2) gpcr receptor will activate adenylase cyclase
3) atp turned into camp which activates PKA
4) pka activates and phosporylates perlipin
4) atgl cuts tag into dag
5) HSL is phosporylated which cuts dag to mag

in the fed state: insulin receptor activates protein phosphatase which dephosporylates and inactivates HSL

37
Q

What is the new lipase that is evedient from a HSL knock out mice?

A

ATGL- adipose triglyceride lipase

38
Q

What coats lipid droplets to regulate lipolysis by controlling the access to HSL?

A

Perilipin

- over expression of perilipin inhibits lipolysis and its knockout has reverse effects

39
Q

FA oxidation steps

A

Phase 1: fatty acid activation (occurs in cytosol)

phase 2: beta oxidation (occurs in matrix)

40
Q

steps for FA to enter mitochondria

A

1.Fatty Acyl CoA Synthetase-

located on the outer membrane of cytoplasm of mitochondria it turns a FA into FA-COA

2)2.Carnitine palmitoyltransferase I- (CPT-I), {also call carnitine acyltransferase}

  • Located in intermembrane space
  • Transfers Fatty Acyl from FA-CoA to Carnitine
  • Forms FA-Carnitine
  • Rate-limiting enzyme in FA degradation
  • Inhibited by Malonyl CoA

3.Carnitine-acylcarnitine translocase- (CACT)

  • Antiporter: FA-carnitine (in) ↔ carnitine (out)
  • Moves FA-carnitine into intermembrane space

4.Carnitine palmitoyltransferase II- (CPT-II)

  • Located in the inner mt-membrane
  • Transfers Fatty Acyl from FA-carnitine to CoA
  • Forms FA-CoA
  • FA-CoA is now in the mt-Matrix
41
Q

Phase I- Transport of FA into Mitochondria

A
  • SCFA and MCFA can diffuse in the mitochondria without carnatine
  • long chain and very long chain need carnatine shuttle (note VLCFA are oxidized in the peroxisomes first and then are turned into LCFA and then brought into the matrix)
42
Q

Phase II Beta Oxidation

A
  1. Oxidation - Acyl CoA Dehydrogenase (ACAD) –> makes FADH2
  2. Hydration
  3. Oxidation –> MAKES NADH
  4. Thiolysis
43
Q

Inherited defects in which ACAD is most common

A

MCAD

44
Q

How do do beta ox with odd number FA

A
  • Metabolized until Propionyl-CoA remains (3 carbons)
    1. Propionyl CoA Carboxylase uses ATP to carboxylate to Methylmalonyl-CoA
    2. Methylmalonyl CoA Mutase generates Succinyl-CoA from Methylmalonyl-CoA

Succinyl-CoA enters TCA cycle

45
Q

How to do beta oxidation with unsaturated FA

A
  1. Metabolized until unsaturation is reached
  2. Reductase reduces double bond
  3. Isomerase moves the disruptive bond
46
Q

VLCFAs (>20 Cs) and Peroxisomal b-Oxidation

A
  • VLCFA’s do multiple beta oxidation in peroxisomes
  • first step is catalyzed by FAD containing Acetyl CoA oxidase which will produce H2O2 to protect against pathogens
  • once you hit 20 carbons it is transported to matrix for the rest
47
Q

Ketone Bodies

A
  • Fasting and starvation causes beta oxidation
  • DM do this because they cant take up glucose

They are 3 water soluble compounds:

  1. Acetoacetate
  2. b-Hydroxybutyrate
  3. Acetone

Produced in Liver Only: (in the mitochondrial matrix of hepatocytes)

During starvation these are made and exported in the blood that can then travel to other sites in the body and be used for the production of A-CoA

48
Q

MCAD Deficiency

A

A disorder of FA-b-oxidation that impairs breakdown of MCFAs

  • Autosomal recessive
  • Incidence – 1:12,000, most prevalent in Northern European Caucasians
  • Leads to secondary carnitine deficiency, due to excessive excretion of MCA carnitines in urine
  • C8 FA accumulates in liver, poisonous, interferes with urea cycle, elevated levels of ammonia

.Patients depend on glucose for energy source

49
Q

If you increase gluconeogenesis

A

you will reduce and run out of oxaloacetate

50
Q

patahlogical ketosis

A

occurs when glucagon/insulin ratio is increased, favoring FA breakdown.

51
Q

ACC regulation

A

-inactive as a dimer but active as a polymer
allosterically regulated by:
-citrate (stimulated)
-LC fatty acid (inhibited)
when dephosporylated it is activated state:
-insulin

When phos its in an inactive state:
-epi, glucagon, AMP

-INDUCTION/REPRESSION: gene expression upregulated by high carb low fat diet

52
Q

Diabetic Ketosis

A
  1. Glucose is not taken up
  2. OAA levels drop thus slows down the TCA CYCLE
  3. FREE FA ARE RELEASED TO THE LIVER AND KETONE BODIES ARE made
  4. the blood pH drops
  5. coma/deat

SFM (31 decks)

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