Fat Metabolism: Degradation

Fat Metabolism: Degradation

Physiological Pathway of Lipid Oxidation:

Lipolysis:

Hydrolysis of triacyglycerol to fatty acids and glycerol in the cytoplasm. Occurs primarily in adipose tissue but also in liver and muscle.

Hormone-Sensitive Lipase: catalyzes intracellular lipolysis

Lipoprotein Lipase: catalyzes hydrolysis of circulating triacylglycerols

Overview of Hepatic Fatty Acid Degradation:

FA = fatty acid

LPL = lipoprotein lipase

FABP = fatty acid binding protein

[1] Free fatty acids bound to albumin are released and delivered via the blood to tissues (i.e. liver).

[2] The lipoprotein system also delivers fatty acids to the liver and other tissues.

[3] Fatty acids w/in cell bound to fatty acid binding protein.

[4] Fats may also be derived by synthesis (lipogenesis) or breakdown of triacylglycerols or phospholipids. These fats are then activated to their acyl CoA form by acyl CoA synthetase (ACS).

[5] Once in an "acyl CoA" form it is converted into a carnitine derivative for transport into the mitochondria.

[6] It is then subjected to b-oxidation.

[7] Acetyl CoA produced by b-oxidation feeds into the citric acid cycle for energy production.

Mitochondrial Uptake and b-Oxidation of Fatty Acids

Carnitines Role in Mitochondrial Fatty Acid Transport:

[1] The product of acyl CoA synthetase, (ACS) long-chain acyl CoA, cannot pass through the inner mitochondrial membrane.

[2] So, it is transformed by carnitine palmitoyl transferase I (CPT-I) to acylcarnitine. (-) Malonyl CoA (lipogenesis)

[3] Carnitine-acylcarnitine translocase acts as a membrane carnitine "exchange transporter".
[4] Acylcarnitine goes in and a carnitine comes out.

The acylcarnitine reacts with CoA via carnitine palmitoyl transferase II (CPT-II), attached to the inner membrane.

Acyl CoA is reformed in the mitochondrial matrix and carnitine is liberated.

Deficiencies in CPT's lead to considerable muscle weakness, as fatty acids are a major fuel during muscle use.

Fatty Acid Activation and Transport

b-Oxidation of Free Fatty Acids With an Even Number of Carbons:

Reactions 2 through 5 recycle to remove consecutive 2-carbon units. On the final cycle, 2 acetyl CoA molecules are formed. Thus, a 16 carbon fatty acid needs to cycle only 7 times.

Energy Production:

35 ATP (7 cycles b-oxidation, NADH and FADH₂ produced)

72 ATP (6 cycles b-oxidation, accounts for 12 carbon atoms)

2 Acetyl CoA: 24 ATP (produced in the last step from the remaining 4 carbons, enters TCA cycle)

Total: 131 ATP

Odd Chain Fatty Acids:

Endproducts are propionyl CoA and acetyl CoA caused by cleavage of a 5-carbon fatty acid during the final cycle.

Propionyl CoA Carboxylase:

Propionyl CoA + ATP + CO₂ -----> Methylmalonyl CoA + AMP + PP_i

Methylmalonyl CoA Mutase:

Methylmalonyl CoA -----> Succinyl CoA (enters Citric Acid Cycle)

Energy Production:

35 ATP (7 cycles b-oxidation, NADH and FADH₂ produced)

72 ATP (6 cycles b-oxidation, accounts for 12 carbon atoms)

Acetyl CoA + 1 Succinyl CoA 18 ATP (produced in the last step from the remaining 5 carbons, enters TCA cycle)

Total: 125 ATP

-1 ATP = 124 ATP

Comparison of Fatty Acid b-Oxidation and Synthesis

Ketone Metabolism (Ketogenesis):

Occurs in liver when acetyl CoA production exceeds the limits of its oxidation in the citric acid cycle --------> starvation or uncontrolled diabetes.

Conditions Favoring Ketoacidosis:

Ketone Body Formation in Liver:

Normal Prevention of Ketoacidosis:

Insulin whose release is promoted by ketone bodies, inhibits lipolysis to decrease the supply of fatty acids and thus curtail ketogenesis ---> prevent ketoacidosis

Ketone Body Oxidation: long-term starvation or ketoacidosis

Tissues that can use ketones as "fuel": brain, muscle, kidney, intestine

b-hydroxybutyrate + NAD⁺ ---> NADH + acetoacetate

acetoacetate + succinyl CoA ---> acetoacetyl CoA + succinate

acetoacetyl CoA + CoA ---> 2 acetyl CoA