L21: Lipid Metabolism II Flashcards

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1
Q

Is the liver a site for fat storage? What does it store?

A
  • It is a site for fat synthesis, but not for storage. Pathology = storage of fat in liver - It serves as a site for many things including glycogen.
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2
Q

Where does FA synthesis occur?

A
  • Cytoplasm
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3
Q

Explain mechanism that brings acetyl-CoA to cytoplasm from mitochondrion that preceeds FA synthesis?

A
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4
Q

What are the 2 sources of cytosolic NADPH?

A
  • PPP via G6PD - Conversion of malate to pyruvate via malic enzyme
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5
Q

What is the enzyme that commits acetyl-CoA to FA synthesis? What does this reaction do?

A
  • Acetyl-CoA carboxylase, which converts acetyl-CoA to malonyl-CoA
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6
Q

Describe the synthesis of FAs.

A
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7
Q

What molecule does FA synthesis begin with? What are the second, third… molecules used?

A
  • FA synthesis begins with acetyl-CoA and then joins with malonyl CoA during round 1 - Round 2-X begins with malonyl-CoA.
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8
Q

Explain the process of FA elongation from a 16 carbon molecule. Why is this necessary? Where does it occur?

A
  • Cytoplasm has FA synthase that synthesizes FAs to 16 carbons = palmitate (16:0), which is a saturated molecule. - Many lipid structures in the body are longer than 16 carbons - Elongation occurs in mitochondrial as shown here:
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9
Q

Explain the process of FA desaturation. Why is this necessary? Where does it occur?

A
  • Many lipids in body are not saturated. - Desaturation of FAs occur in endoplasmic reticulum as shown here:
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10
Q

Describe reactions that form triacylglycerols.

A
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11
Q

How is glycerol (or G3P) synthesized? What is this a precursor to?

A
  • Glycerol-phosphate-dehydrogenase takes DHAP and converts it into glycerol-3-phosphate, which is precursor to TAGs.
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12
Q

What is the committed step in TAG synthesis? What are TAG synthesis precursors used for?

A
  • Committed step is conversion of phosphatidic acid to 1,2 diacylglycerol via phosphatidate phosphatase. - Phosphatidic acid can be shunted into lipid membrane synthesis pathways instead of going down TAG synthesis pathway.
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13
Q

Discuss regulation of FA (TAG) synthesis, degradation and mobilization/release

A
  1. ) FA synthesis
    - Well-fed state:
    a. ) insulin: induces expression of acetyl-CoA carboxylase, FA synthase, malic enzyme and G6PD long-term basis
    b. ) insulin: activates acetyl-CoA carboxylase and glycolysis (both via phosphoprotein phosphatase, which removes phosphates) – short term basis
    c. ) citrate: activates FA synthase
    - Starvation
    a. ) absence of insulin: levels of acetyl-CoA carboxylase, FA synthase, malic enzyme and G6PD fall
    b. ) glucagon: caused cAMP and PKA activity to rise.
    c. ) PKA: inactivates acetyl-CoA carboxylase by phosphorylation, inhibits glycolysis
  2. ) FA degradation
    - Limiting step = bringing FA into mitochondria via carnitine shuttle / CPTI/II. This is inhibited by malonyl-CoA in well-fed state when FA synthesis is occurring.
  3. ) FA mobilization
    - High glucagon/low insulin stimulates mobilization: In fasting state, glucagon raises cAMP levels and activates PKA. PKA activates perilipin and hormone sensitive lipase both by phosphorylation (remember, glucagon acts via phosphorylation). This results in FAs being clipped off glycerols allowing them to become FFAs diffuse out of adipose tissue and move to other tissues. In other tissues they move into mitochondria via CPT I shuttle mechanism which are active as malonyl-CoA is low (this should only be occurring in starved state) and proceed through beta-oxidation.
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14
Q

Draw function of insulin in regulation of FA (TAG) synthesis.

A
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15
Q

Draw function of glucagon presence (insulin absence) in regulation of FA synthesis.

A
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16
Q

Are TAGs synthesized in the fasting/starved or well-fed state? Explain

A
  • They are synthesized in both states. Why? In fasting state, there are far more FAs circulating than can be used, a mechanism to ensure abundant supply of FAs.
17
Q

Describe the TAG-FA cycle between adipose and liver cells. Why is this necessary?

A
  • In the fasting state, there are far more FAs circulating than can be used. - The liver resynthesizes TAGs for export to adipose tissue via the following mechanism:
18
Q

Describe the composition of lipid droplets?

A
  • Lipid droplets are packages containing TAGs. These are surrounding by a protein coat composed of many proteins including perilipin. Perilipin acts as protector of the TAGs stores and prevents lipases, such as hormone sensitive lipases from degrading TAGs into FFA and glycerol. When perilipin is phosphorylated, it allows lipases to do this, but not when dephosphorylated.
19
Q

What are the three factors that lead to development of fatty liver in chronic alcoholism?

A

1.) alcohol metabolism in liver generates NADH and acetyl-CoA. High concentration of NADH blocks TCA cycle enzymes and forces acetyl-CoA into FA synthesis. 2.) Beta-hydroxyacyl dehydrogenase (beta-oxidation enzyme) requires NAD, which is at low concentration during alcohol metabolism. This means that FA breakdown by liver is slowed down and leads to accumulation of fat. 3.) Damaged liver tissue has reduced capacity to synthesize VLDLs to export FAs to adipose tissue

20
Q

What is the function of diacylglycerol acyltransferase (DGAT) inhibitors?

A
  • Inhibits synthesis of triacylglycerol