Lipolysis of Triglycerides in Adipose Tissue

• Lipolysis involves the breakdown of triglycerides (TG) into fatty acids (FA) and glycerol.
• Triglycerides are released from adipose tissue between meals, during overnight fasting, and during strenuous exercise.
• Hormone-sensitive lipase initiates lipolysis.

Lipolysis of Triglycerides in Adipose Tissue

• Glycerol is not degraded by adipose tissue due to the absence of glycerol kinase.
• Glycerol is transported by the blood to the liver.
  • Once there it can be used for TAG synthesis, glycolysis, or gluconeogenesis.
• Fatty acids move through the adipocyte cell membrane.
• They then bind to albumin in the plasma.
• After binding they are then transported to tissues, excluding erythrocytes and the brain.
  • The tissues then oxidize for energy.

Regulation of Lipolysis

• Fasting leads to a decrease in blood glucose.
  • This increases glucagon levels, which in turn increases cyclic AMP (c-AMP).
  • Increased c-AMP then leads to lipolysis.
• Stress or strenuous exercise increases adrenaline levels followed by a rise in c-AMP, which promotes lipolysis.
• In a fed state, blood glucose increases, leading to increased insulin and decreased glucagon levels.
  • This results in decreased lipolysis.

Regulation of Fatty Acid Release by Glyceroneogenesis

• During fasting conditions, free fatty acids (FFA) are recycled, and glycerol 3-phosphate is regenerated in the adipocyte.

Degradation of Fatty Acids

• Greatest flux through pathway occurs during starvation.
• Hormonal state favors a low insulin/glucagon ratio.
• Major Tissue Site degradation occurs is the muscle and liver.
• The Subcellular Location is primarily the mitochondria.
• Carnitine transports acyl/acetyl groups between mitochondria and cytosol.
• Coenzyme A provides phosphopantetheine-containing active carriers.
• NAD+ and FAD (oxidation) act as oxidation/reduction coenzymes.
• Acetyl CoA is a product of β-oxidation and acts as a two-carbon donor.
• Malonyl CoA inhibits carnitine palmitoyltransferase-I.
• The product is Acetyl CoA.
• Repetitive four-step degradation involves dehydrogenation, hydration, dehydrogenation, and thiolysis.

Fatty Acid Oxidation / β-Oxidation

• Fatty acids are converted into FADH2, NADH, and acetyl CoA.
• This occurs under aerobic conditions in the mitochondria.
• Requires carnitine shuttle
• Reversible
• Source of carnitine: diet / is synthesized from lysine

Steps in β-Oxidation

• Fatty acid activation occurs in the cytosol, converting fatty acids to fatty acyl CoA using fatty acyl CoA synthetase (thiokinase).
• Fatty acyl CoA is transported into the mitochondria via the carnitine shuttle.
• Reactions then take place in β-oxidation
  • Oxidation to alkene
  • Hydration to alcohol
  • Oxidation to carbonyl
  • Cleavage

Fatty Acid Activation and Carnitine Shuttle

• Long-chain fatty acyl CoA is transported from the outside to the inside of mitochondria.
• Fatty acids with fewer than 12 carbons can cross the inner mitochondrial membrane without the help of carnitine or the carnitine palmitoyltransferase (CPT) system.
• In the mitochondria, fatty acids are converted to CoA derivatives by matrix enzymes and are oxidized.

β-Oxidation Reactions

• Four Important Steps:

  • Oxidation (FADH2)
  • Hydration
  • Oxidation (NADH)
  • Thiolytic cleavage

• Calculating Number of β-oxidation Cycles:

  • Number of β-oxidation cycle = (n/2) - 1
  • n=number of carbon
  • Every acetyl CoA provides 12 ATP when converted to CO2 and H2O by the TCA cycle, with a yield of 96 ATP
  • 7 FADH2, each provide 2 ATP when oxidized by CoQ of the electron transport chain with a yield of 14 ATP
  • 7 NADH, each provide 3 ATP when oxidized by Complex I of the electron transport chain, with a yield of 21 ATP

Other Types of β-Oxidation

• Fatty acids with an odd number of carbons, such as propionyl CoA, undergo a modified process.
• Unsaturated fatty acids yield less energy compared to saturated fatty acids.
• Very long-chain fatty acids (VLCFA) with more than 22 carbons undergo preliminary β-oxidation in peroxisomes.

Alpha-Oxidation

• Branched-chain, 20 carbon fatty acids, such as phytanic acid, are not substrates for acyl CoA dehydrogenase.
• Instead, they are hydroxylated by phytanoyl CoA α-hydroxylase (PhyH).
• For 20 carbon chains, one carbon is converted to CO2.
• 19 carbon pristanic acid is activated to its CoA derivative and undergoes β-oxidation.

Ketone Bodies

• Ketone bodies—acetoacetate, 3-hydroxybutyrate, and acetone—are produced in the liver mitochondria from acetyl CoA (resulting from fatty acid oxidation).
• Acetoacetate and 3-hydroxybutyrate are released into the blood for use (ketolysis) by peripheral tissues.
• In the tissues, acetoacetate, and 3-hydroxybutyrate can be reconverted to acetyl CoA, and oxidized by the tricarboxylic acid (TCA) cycle.
• Ketone bodies are an important source of energy during fasting.

Ketogenesis in Liver

• During fasting, fatty acids increase in the liver.
• This leads to an increase in acetyl CoA in mitochondria due to fatty acid degradation.

Ketolysis in Peripheral Tissues

• During fasting, are when ketone bodies highly produced.