Fat Metabolism: Regulation and Integration

Regulation of Hormone-Sensitive Lipase (Lipolysis) : "Fasted" State

Hormone Sensitive Lipase, Phosphorylated- Active

Hormone Sensitive Lipase, Dephosphorylated- Inactive

Regulation of Acetyl CoA Carboxylase (Lipogenesis): "Fed" State

Acetyl CoA Carboxylase, Allosteric Control:

Polymer- Active

Monomer- Inactive

Citrate ----> Polymerization ----> "Active" (lipogenesis)

Palmitoyl CoA ----> Depolymerization ----> "Inactive"

Acetyl CoA Carboxylase, Covalent Modification:

Glucagon, Epinephrine (low glucose) ----> Phosphorylation ----> "Inactive" (while promoting lipolysis)

Insulin ----> Dephosphorylation ----> "Active"

Acetyl CoA Carboxylase, Induction / Repression:

High CHO and Low Fat Diets ----> "Inductive" (increased synthesis)

High Fat Diet and Fasting ----> "Repression" (decreased synthesis)

 

Coordinated Control of Fat Synthesis and Breakdown via Acetyl CoA and Malonyl CoA:

 

Interrelationship of Fat and CHO Metabolism When Glucose is High:

Conditions Favoring Fat Synthesis (Lipogenesis):

CHO intake ----> Elevated Blood Glucose ----> Insulin High, Glucagon Low

Insulin (-) hormone sensitive lipase; (+) glucose utilization (glycolysis) and acetyl CoA production for lipogenesis

Citrate (+) acetyl CoA carboxylase

Malonyl CoA (-) carnitine palmitoyl transferase I (decreasing b-oxidation)

Conditions Favoring Lipolysis / b-Oxidation:

Starvation ----> Low Blood Glucose ----> Insulin Low, Glucagon High ----> (+) Lipolysis (free fatty acids for liver)

"Fight or Flight" ----> Epinephrine High ----> (+) Lipolysis (energy for muscle)

Low Blood Glucose ----> (+) gluconeogenesis (decreasing "C" supply for lipogenesis)

Acetyl CoA Carboxylase- phosphorylated ("Inactive")

CPT I- "Active" (due to decrease in Malonyl CoA)

Interrelationship of Fat and CHO Metabolism When Glucose is Low:

Starvation:

Fatty Acids are Oxidized in Liver which Promotes Gluconeogenesis by:

(a) providing energy

(b) generating NADH

(c) forming acetyl CoA to activate pyruvate carboxylase

(d) producing citrate which increases F-1,6-BPase activity

Comparison of Energy Yields and Oxygen Consumption for Fats vs. Ketones vs. Carbohydrates:

1 NADH = 3 ATP

1 FADH2 = 2 ATP

Palmitate (3 molecules = 48 "C"s)

Step 1: b-oxidation to acetyl CoA (6 cycles); (1 NADH + 1 FADH2)/cycle

Step 1cont'd: 7 x 3 molecules 21 FADH2+ 21 NADH ==> +105 ATP; -42 O atoms

Step 2: Acetyl CoA oxidation via TCA cycle; (3 NADH, 1 FADH2, 1 GTP) / Acetyl CoA

Step 2 cont'd: 8(6 + 2) x 3 molecules: 24 Acetyl CoA ==> +288 ATP; -96 O atoms

Step 3: Acyl CoA formation (ATP --> AMP + PPi; 2 ATP / molecule)

Step 3 cont'd: 2 x 3 molecules: ==> -6 ATP

b-hydroxybutyrate (12 molecules = 48 "C"s)

Step 1: oxidation to acetoacetate via b-hydroxybutyrate DH

Step 1 cont'd: 1 x 12 molecules: 12 NADH ==> +36 ATP; -12 O atoms

Step 2: Acetoacetate cleaved to 2 acetyl CoA ( loss 1 GTP due to succinyl CoA diversion)

Step 2 cont'd: 1 x 12 molecules: -12 GTP ==> -12 ATP

Step 3: Oxidation of acetyl CoA via TCA cycle

Step 3 cont'd: 2 x 12 molecules: 24 Acetyl CoA ==> +288 ATP; -96 O atoms

Glucose (8 molecules = 48 "C"s)

Step 1: Aerobic glycolysis, 2 NADH (mal-asp shuttle) + 2 ATP/glucose

Step 1 cont'd: 2 x 8 molecules: 16 NADH + 16 ATP ==> +64 ATP; -16 O atoms

Step2: PDH

Step 2 cont'd: 2 x 8 molecules: 16 NADH ==> +48 ATP; -16 O atoms

Step 3: Oxidation of acetyl CoA via TCA cycle

Step 3 cont'd: 2 x 8 molecules: 16 Acetyl CoA ==> +192 ATP; -64 O atoms

 

Fuel Total ATP O2 Used ATP/"C" CO2/O2 ATP/"O" Atom
Palmitate 387 69 8.12 0.7 2.80
Ketone 312 54 6.50 0.9 2.89
Glucose 304 48 6.33 1.0 3.17

Note: ATP / "O" Atom is a measure of "fuel" efficiency

Fats: produce more ATP per "C", however it is at the expense of more oxygen (ATP / O atom), thus the respiratory quotient (CO2 / O2) is the lowest.

Ketones: in starvation increase the amount of O2 needed to burn fuel to CO2 (CO2 / O2) only a small amount as compared to fats. The energy yield per carbon for ketones is similar to glucose. The brains energy needs and O2 availability can be met nearly as well by ketones, as by glucose.

Glucose: is the better fuel under conditions of O2 limitation, giving more ATP / O atom.

 

© Dr. Noel Sturm 2015