Lipolysis, FA Oxidation, Ketogenesis

Question 1

Lipolysis:

Where it occurs
Function
Enzymes
Products and fates

Answer 1

Where: Adipose

Function: mobilize fat via hydrolysis

1. HSL: TAG–> FFA, Glycerol
   - Generates twice as many FAs as needed
   - Excess FFA resynthesized in liver and placed in VLDL

Enzyme:

• RATE LIMITING: Hormone Sensitive Lipase (TAG–> FFA + Glycerol)
• Fatty Acyl-CoA Synthetase (FFA–> Fatty Acyl CoA)

Products and Fates:
-FFA: fuel for tissues with mito in fasting state, except brain
Glycerol

Question 2

HSL Regulation

Answer 2

Regulated by insulin and epi via phosphorylation

Phosphorylated:

• Active
• Fasting state
• Low insulin, high epi.
• Epi phosphorylates via PKA

Dephosphorylated:

• Inactive
• Fed state
• Insulin RTK resulting in dephosphorylation

Question 3

Clinical Note: Niacin and HSL

Answer 3

niacin inhibits HSL, decreases lipolysis

decreased production of VLDL and LDL

Question 4

FFA Transport and Activation

Answer 4

1. FFAs released from adipose
2. enter blood stream and carried via serum albumin
3. uptake by muscle, liver, tissues mediated by membrane bound FA carrier
4. FA in cell activated by fatty acyl-CoA syntheTASE in cytosol by attaching CoA
5. Fatty acyl CoA can enter beta oxidation or resynthesized to TAG

Question 5

Beta Oxidation:

When it occurs
Where it occurs
Function
Enzymes
Products & Fates

Answer 5

FFAs–> ACoA, NADH, FADH2

When: FAST, low I/G ratio or high Epi

Where:
-Tissues - Liver and mito tissues
-Cell location - mito matrix
NOT BRAIN - FA cannot cross BBB

Function:
-supplies majority of energy during fasting

Enzymes:
-Carnitine Shuttle: CPT-I (RATE LIMITING), translocase, CPT-II

Products & Fates:

• ACoA: TCA cycle and ketogenesis
• NADH and FADH2: ETC for ATP production

Question 6

Carnitine Shuttle (CPT-I, translocase, CPT-II)

Answer 6

Fatty Acyl CoA (cyto)–>Fatty Acyl CoA (mito)

Fatty Acyl CoA into intermitochondrial membrane space

CPT-I replaces CoA for carnitine in membrane space

Translocase brings carnitine FA to inner mito membrane

CPT-II reattaches CoA to resynthesize Fatty Acyl CoA

Question 7

Regulation of CPT-I

Answer 7

RATE LIMITING ENZYME

inhibited by malonyl CoA in FED state

malonyl CoA produced by ACC in lipogenesis

Keeps new FA in cytosol to prevent oxidation during fed state

Question 8

Beta Oxidation process

Answer 8

FAs shortened 2 C at a time in a series of 4-step reactions

Generates 3 products:
FADH2, NADH & ACoA

ACoA enters TCA resulting in more NADH and FADH2

ACoA can also enter ketogenesis

Question 9

Ketogenesis

When it occurs
Where it occurs
Functions
Enzymes
Products and Fates

Answer 9

Acetyl-CoA –> acetoacytate, beta hydroxybutyrate, acetone

Fasting state, low I/G, High Epi

Where: Liver only, mitochondrial matrix

Functions:

• convert FAs (hydrophobic) to ketone bodies (hydrophilic)
• export only: liver cannot oxidize ketone bodies
• oxidized to ACoA in brain, muscle and fetus for energy

Enzymes:
HMG-CoA Synthase (mito)

Products:
Acetoacetate, beta hydroxybutyrate, acetone

Question 10

TCA Cycle in fasted state

Answer 10

Slow

Isocitrate dehydrogenase (Rate limiting for TCA cycle) is inhibited by high levels of NADH (b oxidation) and ATP (ETC complex 5)

More ACoA enters ketogenesis instead of TCA

Question 11

HMG CoA Synthase (mito) Regulation

Answer 11

controlled by substrate availability/ [ACoA] in mitochondria

Question 12

Ketone Oxidation (ketolysis) in extra hepatic tissue

Answer 12

Liver cannot convert ketone bodies to ACoA, so therefore cannot oxidize the ketones it produces

Ketone bodies outside of liver are converted to ACoA, which can then enter TCA cycle