Degradation of Fatty Acids

Degradation of Fatty Acids

Why Fat, Not Carbohydrates?

  • Fats are more reduced, yielding 9 kcal per gram compared to 4 kcal per gram for carbohydrates.

  • Fats are hydrophobic and can be stored without water, whereas carbohydrates are hydrophilic and bind water (1 gram carbohydrate binds 2 grams of H2O).

  • Triacylglycerols (TAGs) are the major energy reserve in the body, offering more efficient energy storage.

Fatty Acids as Fuels

  • Fatty acids are a major fuel for tissues; glucose is the major circulating fuel.

  • Fuel usage over 12 hours:

    • Fatty Acids (FA): 60 grams (540 kcal)

    • Glucose: 70 grams (280 kcal)

Release of Fatty Acids from TAG

  • Hormonal regulation:

    • Acetyl CoA carboxylase, crucial for fatty acid synthesis, is inhibited by the same signaling pathway as glucagon or epinephrine.

    • Perilipin coats fat droplets, blocking HSL (hormone-sensitive lipase). Phosphorylation by PKA releases perilipin.

Glycerol Metabolism in Liver and Adipose Tissues

Liver

  • Glycerol kinase phosphorylates glycerol to glycerol 3-phosphate.

  • Glycerol 3-phosphate can then be converted to dihydroxyacetone phosphate via glycerol 3-phosphate dehydrogenase, linking glycerol metabolism to glycolysis.

Adipose Tissue

  • Adipose tissue lacks glycerol kinase.

  • Glycerol 3-phosphate is produced from dihydroxyacetone phosphate, an intermediate in glycolysis, using glycerol 3-phosphate dehydrogenase.

  • Insulin promotes the uptake of glucose via GLUT-4, increasing the availability of dihydroxyacetone phosphate.

β-oxidation of Fatty Acids

  • Fatty acids are transported in the blood bound to albumin.

  • They are degraded by oxidation at the β-carbon, followed by cleavage of two-carbon units.

β-Oxidation Overview

  • The process involves the following:

    • Activation of a fatty acid by joining it with Coenzyme A.

    • Sequential removal of two-carbon units in the form of acetyl-CoA from the fatty acid.

    • The general reaction can be represented as:
      CH3(CH2)n-CH2-CH2-COO^- \rightarrow CH3(CH2)n-CO\sim CoA + CH_3-CO \sim CoA

Activation of Fatty Acids

  • Involves joining a fatty acid with Coenzyme A to form a thioester bond (RCO~SCoA).

  • The reaction occurs in two steps and is catalyzed by thiokinase (acyl CoA synthetase):

    • FA + HSCoA + ATP \rightarrow FA\sim CoA + AMP + PPi

    • PPi + H_2O \rightarrow 2 Pi

    • Overall: FA + HSCoA + ATP \rightarrow FA\sim CoA + AMP + 2 Pi

  • Location:

    • Long-chain fatty acids (LCFA): outer mitochondrial membrane

    • Short- and medium-chain fatty acids: mitochondrial matrix

Transport of LCFA

  • Carnitine shuttle is required to transport long-chain fatty acids into the mitochondrial matrix.

  • The transport system includes:

    1. A carrier molecule (carnitine).

    2. Two enzymes: Carnitine palmitoyl transferase I and II.

    3. Membrane transport protein (translocase).

  • Malonyl-CoA regulates this transport system.

Transport of SCFAs and MCFAs

  • Short-chain fatty acids (SCFAs) and medium-chain fatty acids (MCFAs) directly enter the mitochondria without the carnitine shuttle.

  • In the mitochondria, they are converted to Acetyl-CoA, which enters the Krebs cycle for energy production.

  • Unlike LCFA transport, SCFA and MCFA entry is not regulated by malonyl CoA.

Application: Carnitine

  • Carnitine is synthesized from Lysine and Methionine in the liver and kidney and is also obtained from meat products.

  • Other functions include:

    • Export of branched-chain acyl groups from mitochondria.

    • Binding to acyl groups derived from amino acid metabolism for excretion, acting as a scavenger.

  • The body contains ~97% of all carnitine.

  • Mitochondrial ACC2 regulates fatty acid degradation.

Application: Carnitine Deficiencies

  • Primary carnitine deficiency:

    • Defects in a membrane transporter prevent carnitine uptake by cardiac and skeletal muscles and the kidneys, leading to carnitine excretion.

    • Treatment: carnitine supplementation.

  • Secondary carnitine deficiency:

    • Caused by taking valproic acid (antiseizure), leading to decreased renal reabsorption.

    • Defective fatty acid oxidation leads to the accumulation of acyl-carnitines, which are excreted in urine.

    • Liver diseases leading to decreased carnitine synthesis.

    • CPT-I deficiency: affects the liver, preventing the use of LCFA, resulting in no energy for glucose synthesis during fasting, leading to severe hypoglycemia, coma, and death.

    • CPT-II deficiency: affects the liver, cardiac muscle, and skeletal muscle.

    • Treatment: avoidance of fasting, a diet high in carbohydrates and low in fat, supplemented with medium-chain TAG.

β-Oxidation Steps

  • Step 1: Oxidation by Acyl CoA dehydrogenases

    • Fatty acyl CoA is converted to Enoyl CoA, producing FADH2.

  • Step 2: Hydration by Enoyl CoA hydratase

    • Enoyl CoA is hydrated to form 3-Hydroxyacyl CoA.

  • Step 3: Oxidation by 3-Hydroxyacyl CoA dehydrogenase

    • 3-Hydroxyacyl CoA is oxidized to 3-Ketoacyl CoA, producing NADH + H+.

  • Step 4: Thiolytic Cleavage by thiolase

    • 3-Ketoacyl CoA is cleaved to produce Acetyl CoA and a shortened Fatty acyl CoA.

  • The general scheme:
    CH3(CH2)x-CH2-CH2-C-S-CoA \rightarrow CH3(CH2)x-C-S-CoA + CH_3-C-S-CoA

  • Number of cycles: (n/2)-1

Energy Yield from FA Oxidation

  • Example: Oxidation of C16 Fatty Acid (Palmitic Acid):

    • CH3-(CH2)_{14}-CO-CoA

    • Produces 8 Acetyl CoA, 7 FADH2, and 7 NADH

  • Calculations:

    • 7 FADH2 yields 14 ATP

    • 7 NADH yields 21 ATP

    • 8 Acetyl CoA yields 96 ATP

  • Activation of the Acid consumes 2 ATP.

  • Net yield: 129 ATP per mole of C16 Fatty Acid.

Induction of Gluconeogenesis and Fates of Acetyl CoA

  • Acetyl-CoA, produced from β-oxidation, can have several fates:

    • Ketogenesis: Production of ketone bodies.

    • TCA Cycle: Oxidation in the tricarboxylic acid cycle.

    • Lipogenesis: Conversion back into fatty acids.

  • B-Oxidation of fatty acids yields Acetyl-CoA, which can enter the TCA cycle or be used for ketogenesis.

  • Gluconeogenesis is induced, leading to the synthesis of glucose from precursors like pyruvate

Application: MCAD Deficiency

  • There are 4 isozymes of fatty acyl CoA dehydrogenase for SCFA, MCFA, LCFA, and VLCFA.

  • Medium-chain fatty acyl CoA dehydrogenase (MCAD) deficiency is an autosomal-recessive disorder.

  • It is the most common inborn error of β-oxidation (1:14,000 births worldwide), with a higher incidence among Caucasians of Northern European descent.

  • Results in a decreased ability to oxidize MCFAs, leading to a lack of energy, severe hypoglycemia, and hypoketonemia.

  • Treatment: avoidance of fasting, regular and frequent meals and snacks, and a diet high in carbohydrates and low in fat.

Oxidation of Odd-Numbered FAs

  • Starts as cycles of beta-oxidation producing acetyl-CoA and propionyl-CoA

  • If deficient, metabolic acidosis and neurologic manifestations

Unsaturated Fatty Acid Oxidation

Monounsaturated fatty acid β-oxidation

  • But this reaction is skipped resulting in one less FADH2 -> loss of electrons

Polyunsaturated FA

  • Polyunsaturated FA will also need an NADPH-dependent 2,4-dienoyl CoA reductase in addition to the isomerase. -> loss of electrons

Peroxisomal β-oxidation

  • Involves Very Long Chain Fatty Acids (VLCFA) with ≥22 carbons.

  • Zellweger syndrome: a peroxisomal biogenesis disorder

  • X-linked adrenoleukodystrophy: dysfunctional transport VLCFA across the peroxisomal membrane

  • Accumulation of VLCFAs

  • Loss of electrons

  • FAD Containing acyl CoA Oxidase

Peroxisomal α-oxidation of branched chain FAs

  • Phytanic acid, a breakdown product of Chlorophyll, is activated by CoA, transported into the peroxisome, and hydroxylated by phytanoyl CoA α-hydroxylase (PhyH), and carbon 1 is released as CO2.

  • When fully degraded, it generates formyl-CoA, propionyl-CoA, acetyl-CoA, and 2-methyl-propionyl-CoA.

  • Refsum disease is an autosomal-recessive disorder caused by a deficiency of peroxisomal PhyH.

ω-Oxidation

  • A minor pathway of the smooth endoplasmic reticulum (SER).

  • Generates dicarboxylic acids.

  • Upregulated in certain conditions such as MCAD deficiency.

Lipids and Energy

  • TAGs are the body’s major fuel storage reserve.

  • The complete oxidation of fatty acids to CO2 and H2O generates 9 kcal/g of fat, compared to 4 kcal/g for protein or carbohydrate.

Exercise and sources of energy

  • Energy for muscle contraction

  • ATP ADP Anaerobic metabolism

  • Creatine phosphate Creatine Creatine kinase Active Muscle

  • Aerobic metabolism