Lipid Metabolism Fatty Acid Degardation Week 2

Question 1

HOw is energy released from TAGs?

Answer 1

They are hydrolyzed by lipase– either 1. Lipoprotein lipase- for TAGs in plasma or 2. Hormone-sensitive lipase- intiaites TAG hydrolysis in adipose and release prodcuts to plasma

Question 2

Where are lipoproteins lipase located? How do they work?

Answer 2

Lipoprotein lipases (hydroylze TAG in plasma lipoproteins)- are on surface of endothelial cells of capillaries.

They hydrolyzes fatty acids from the 1 or 3 position of TAGs or DiAGs present in chylomicrons or VLDL. THe FA from the hydrolysis binds to albumin or is taken up by tissue.

Needs Apoprotein CII for activation and stumulated by insulin

Question 3

Difference in hydrolysis of TAGs/DiAGs and Monoaclyglycerol

Answer 3

TAGs/DiAGs are hydrolyzed by lipoprotein lipase while monacylglycerol either pass into the cell or are hydrolyzed by serum monoacylglycerol hydrolase.

Question 4

Enzyme that hydrolyzing TAGs from adipose. How does it work?

Answer 4

TAGs in adipose are hydrolyzed by hormone-senstiive lipaes

Acts on the surface on adipose tissue, so when hormone (glucagon, although Epinephrine can stimulate it too) hits the signal that energy is needed, this lipase is active and can liberate FA from glycerol.

FA bind to albumin and are transported for use

Glycerol goes back to liver and can be used for glycolysis or gluconeogenosis

Question 5

Explain how hormone senstive lipase are trigger and mechanism

Answer 5

Glucagon or Epi hit the adipocytes, which upregulates cAMP and PKA so phosphorylates the enzyme, activating enzyme which starts to cleave FA from triglycerols

Question 6

Regulatin of hormone senstive lipase

Answer 6

Upregulate- glucagon, Epipherine

Down regulate-insulin

Question 7

Regulation of Lipoprotein Lipase

Answer 7

The delivery of VLDL and chylomicron must have the CII for notciing

Activated by insulin

Question 8

What organs/systems use FA more? WHy?

Answer 8

Cardiac and muscle because they have high potential energy

When energy is low they use only FA to save glucose for the brain since FA/long chain fatty acids can’t pass into the brain because of the BBB.

Question 9

How are FA activated? What are the steps for beta oxidation?

Answer 9

By conversion to Fatty Acyl CoA by fatty acylCoA synthase located on the OUTER mitochondrial membrane and this requires 1 ATP

Even after activation CPT 1 helps the FA cross the outer mitochondrial membrane which causing a loss of activation

Then the FA is transferred to Carinitine (bound together) and it carries acyl gorup

This helps carry the FA to the mitochondrial matrix where another ATP is used to reactivate the FA for B-oxidation

Question 10

Energy from Beta Oxidation

Answer 10

A palmitate has 16 carbons so could make 8AcetylCoA each of ehich could enter the TCA

Also with every turn you have FADH2 and NADH liberated that can go to terminal oxidation

So you get up to 129 ATP– remember that FA oxidation requires mitochonria and good oxygenation

Question 11

What’s special about small and mediucm FA

Answer 11

They don’t need caritine. They still beed activation to reach Beta oxidation!

Question 12

Four step reactions of Beta oxidation

Answer 12

1. Acyl CoA in the inner mitochondrial membrane (already activated and carried by CPT1, carnitine, and CPT II) is dehydrogenated by one of the 4 acyl CoA Dehydrogenase VLCAD – for very-long chain FAs (C20-24)– works in peroxisomes only
   LCAD – for long chain FAs (C12-18)
   MCAD – for medium chain FAs (C6-10)
   SCAD – for short chain FAs (C4-6)
2. Fatty acyl CoA—- acyl CoA DH–> Enoyl CoA
3. Enoyl— enoyl COA hydratase—> 3-L hydroxyacyl CoA (hydrolyzing the trans double bond)
4. 3-L hydroxyacyl CoA— 3-L hydroxyacyl CoA DH—> B-ketoacyl-CoA
5. Thiolase cleaves off a two carbon fragment

Question 13

Dicuss effects of missing a Acyl CoA DH

Answer 13

This is the family of DH that is the first step of beta oxidatoin. If they are missing there is fatty acid in the liver and can cause hepatic mitochondrial damage and impaired liver function.

When There is an accumulation of FA is accumulates then spill sback to the liver. We will see some FA chains bound to the carnitine— carnitine bound FA is an early indicator that the DH is missing

Question 14

Regulation of Beta Oxidation

Answer 14

Upregulated by- presense of cofactos and substrates ad the rate of actyl CoA from the TCA cycle

Carnitine from the matrix to the inner mitochondrial is the rate limiting step

**Malonyl CoA (first activated unit in FA acid synthesis) inhibits CPT1 (carry FA from the cytosol into the matrix) **– this is only in cells that can produce FA- liver and adipose tissue

Question 15

Energetics of Beta-Oxidation

Answer 15

Each round makes 1 acrtyl CoA, 1 NADH, 1FADH2

making 8AcCoA + 7 FADH + 7NADH (we only do 7 rounds because the last product comes from a C4 is cleaved into two)

Question 16

Special pathways- what do we do with odd chain fatty acids?

Answer 16

In degardation we end with a 3 carbon chain (Propionyl CoA)- which can be modified (carboxylated to methylmalonyl CoA and rearranged to Succyl CoA) which can be used for gluconeogenosis

This requires Biotin and B12 to make Succinyl CoA

Question 17

Special pathways- what do we do with unsaturated fatty acids in degradation?

Answer 17

THe kink is normally in a cis conformation (if it’s in trans the enzymes can work on it) so we usean isomerase to switch the cis to trans.

Question 18

Discuss degradation of polyunsaturated FA

Answer 18

THey have several double bonds and they need extra enzymes that require NADPH (from the PPP)

Question 19

Explain waht happens to VLC FA

Answer 19

Very long chain FA (over 20) can’t enter the mitochondria so they go peroxisomes for Beta oxidation shortening to 16. which intially produces FADH2.

Catalase reduces water - good indicator of where the perioxisomes are.

There is no energy gerneration in the perioxisomes– its just for modication and removal.

Question 20

What do perixisomes handle

Answer 20

Branched beta chain oxidation and very long chain beta oxidation

Question 21

What is lapha oxidation?

Answer 21

Mainly in the ER and mitochondria and hydroxylate fatty acids through the cytochrom P450 system, need NADPH and O2

Question 22

What are ketone bodies

Answer 22

Water slouble lipid based energy that are mainly acetoacetic acid and produced in the liver (and kidney) within the mitochondrial matrix

Question 23

Production of ketone bodies

Answer 23

3 acetyl CoA—–> hydroxymethylgltaryl coenzyme A (HMG CoA)

HMG CoA— HMG CoA lyase—> acetoacetic acid and acetyl CoA

acetoacetic and hydrobutyrate are the two main precursors to the ketone—when in circulation during fasting they can spontaneously produce acetone (often happens in diabetics)

Question 24

Usage of ketone bodies

Answer 24

They go into circultoin and taken up tissues nad cell that need it minaly the CNS under starvation but muscle cells can also channel ketone bodies to Beta Oxidation

Question 25

Fate of AcCoA in the liver

Answer 25

If in the mitochondria we can use it to in TCA for energy (and in liver for ketone synthesis)

When under insulin we would acetyl CoA will be used for Choelsterol and FA synthesis