Fat Metabolism: Regulation and Integration

Fat Metabolism: Regulation and Integration

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

Phosphorylated- Active

Dephosphorylated- Inactive

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

Allosteric Control:

Polymer- Active

Monomer- Inactive

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

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

Covalent Modification:

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

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

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 bisPase activity

Comparison of Energy Yields and Oxygen Consumption:

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.

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

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.