Lipid Metabolism During Exercise

Introduction1.) Energy Density

2.) Polar explorers/sled dogsAmerican Indians (pemican)

3.) Migrating fish and birds

4.) 3 sourcesplasma FFA from adipocytes (large > 50,000 kcals)intramuscular TG (2,000 -3,000 kcals)plasma TG (very small role during exercise in humans)

5.) Destabilizing effect on membranes High IMTG (obesity, type-II diabetes) linked with insulin resistance in muscle.

Storage and Mobilization of Triglycerides

Adipose Tissue Lipolysis

• Glycerol release, no Glycerol Kinase in adipocyte or muscle

, , Insulin, Lactate

re-esterification

FFA

Passive vs. Carrier-mediated

Fatty acid binding protein (FABP)EPI Insulin

B increases cAMP

Alpha decreases cAMP

Insulin activated PDE thus decreases cAMP

Hormone Sensitive Lipase• Phosphorylated by Protein Kinase A

– becomes active– catabolic in nature

Mechanism:Epinephrine binds to receptor on adipocytethis causes activation of AC – increase in cAMPcAMP activates Protein Kinase A

Insulin counteracts thisdeactivates Protein Kinase A via activation of PP-1, activates PDE which decreases cAMP

Regulation of Hormone-Sensitive Lipase

PKA

C

C

C OH

OH

OH

C C

O

C COH

Dehydration Synthesis

C

C

C C C

O

C CO

Triglyceride

C

C

C OH

OH

OH

+C C

O

COH

Glycerol FFA

H.S. Lipase

Hormone Sensitive Lipase

Adrenoceptor Blockade Schematic

FFA/Blood Glycerol at Rest and Exercise

Exercise 50%

Exercise 50%

Notice the magnitude of the change in FFA vs. glycerol

FFA Transport to Muscle Cells• Fatty Acids from adipose

– transported in blood via Albumin – 3 per– brought to muscle cell at fatty acid binding

receptor proteins– taken into muscle cell

Triglycerides in blood (chylomicrons and VLDL)broken down by lipoprotein lipase in capillary of the muscle before being taken into cell

FA transporters

1. FABPpm

2. FATP

3. FAT/CD36

Higher in ST vs. FT

Training has been shown to increase the amount of FA transporters in the PM.

Fatty Acid Transport Into Mitochondria

• FA can’t cross mitochondrial membrane

Must use carnitine acyl transferase (CAT) system

CAT Ilocated in outer wallBinds carnitine to FA, enabling it to pass inner mem.RATE LIMITING STEP IN FAT UTILIZATION!

CAT IIlocated in mitochondrial matrixremoves carnitine from FA

Fatty Acid Transport Into Mitochondria (cont.)Step 1:

FFA Fatty Acyl CoA(Acyl CoA synthase – in outer wall)

Fatty Acyl CoA Fatty Acyl CarnitineCAT I

Fatty Acyl Carnitine CAT II Fatty Acyl CoA (inside mitochondrial matrix)

Step 2:

Step 3:

*With training, number of mitochondria, CAT I , fat use with exercise.

-Oxidation Cycle

*No rate limiting steps in -Oxidation cycle! Rate limiting step occurs with CAT I.*

OHC C C C

O

FFA

ATP

AMP

CoAS H

H2O

Step 1:

Acyl CoA Synthase

~SC C C

O

CoA

HH

H H Fatty Acyl CoA

Step 2:

~SC C C

O

CoA

HH

H H

Fatty Acyl CoA

FAD

FADH2

Acyl CoA Dehydrogenase

~SC C C

O

CoA

H

H Enoyl CoA

(trans dehydrogenase rx)

**Recall: Fatty Acyl CoA is transported into mitochondria via CAT I & II complex**

~SC C C

O

CoA

H

Enoyl CoA

Step 3:

H2O (add to make 2° -OH)Enoyl CoA Hydrase

~SC C C

O

CoA

H

H

OH

L-Hydroxyacyl CoAH

H

~SC C C

O

CoA

H

H

OH

L-Hydroxyacyl CoAH

Step 4:

NAD

NADH + H

L-Hydroxyacyl Dehydrogenase

(oxidize 2°-OH to keto)

~SC C C

O

CoA

HO

Keto AcylH

()( Carbon)

Step 5:

~SC C C

O

CoA

HO

Keto AcylH()

CoASH

~SC

O

CoA

Acyl CoA~SC C

O

CoA

H

H Acetyl CoA (on to Krebs cycle)

H

Ketothiolase-oxidation? () carbon oxidized from saturated to keto NAD & FAD are reduced!

Energy yield of Palmitic Acid(16 C - FS - FA)

C C C C C C C C C C C C C C C C

7 FADH2 x 2 = 14

7 NADH2 x 3 = 21

8 Acetyl CoA x 12 = 96_

131__-2

129 ATP

Activation with Co ASH

ATP AMP

In CAC:3 NADH

1 FADH

1 ATP

GlycerolC

C

C OH

OH

OH

Glycerol

Glycerol kinase only in liver

ATP ADP C

C

C O~P

OH

OH

Glycerol 3-P

H

NAD

NADH2

(Glycerol P dehydrogenase)

C

C

C O~P

O

OH

DHAP

gluconeogenesis

glycolysis

Muscle Glycogen vs. FFA Expenditure

Substrates Providing Energy

Plasma Triacylglycerol

FABP

VLDL

Chylomicron

- 50%

- 85%LDL

1. 10% of fat use

2. Slow twitch Fast twitch3. LPL activity 1 hr of exercise

2 - 8 hr 2x LPL~~

Blood 80% H2O

FFA - Albumin TriC |C|C

Lipoprotein Lipase

FFA

In VLDL and chilomicrons

Triglyceride Breakdown for EnergyC

C

C O C

O

C C C

Triglyceride

HSL

C

C

C OH

OH

OH

HO C C C C

O

Glycerol FFA

+

Step 1:

Both muscular contraction and Insulin translocate FAT/CD36 from intracellular sites to plasma membrane. Recent studies have found the effects of insulin and muscular contraction to be additive, suggesting separate ICF pools of FA transporters.

Beta oxidation of FA in the mitochondria increases acetyl-CoA

and citrate concentrations.

AMPK prevents formation of malonyl Co-A, which is a allosteric inhibitor of CAT I, thus AMPK increases FFA uptake into mitochondrial matrix

Triglyceride FormationC

C

C OH

OH

OH

HO C C C C

O

GlycerolFFA

H2O(Dehydration Synthesis)

+

C

C

C O C

O

C C C

Triglyceride