Lipid Catabolism

Lipid: A diverse group of organic compounds that are insoluble in water but soluble in organic solvents.
- Simple Lipids: Fatty acids, glycerides which include triacylglycerols.
- Complex Lipids: Include phospholipids and glycolipids.
- Sterols: Such as cholesterol and other related sterols, which play roles in membrane structure and signaling.

Majority of fatty acids in biological systems are found in the form of triacylglycerols (TAGs).
- Solid triacylglycerols: Known as fats (high carbon number, highly saturated).
- Liquid triacylglycerols: Known as oils (low carbon number, less saturated).

Fuel Molecules:
- Stored as triacylglycerols.
- Approximately one-third of energy needs from dietary triacylglycerols.
- About 80% of energy requirements of mammalian heart and liver is met by the oxidation of fatty acids.
- Many hibernating animals, e.g., grizzly bears, rely almost exclusively on fats as their energy source.
Building Blocks:
- Serve as components of phospholipids and glycolipids.
- Precursors for hormones and other signaling molecules.
- Facilitate targeting of proteins to membrane sites (e.g., sex hormones).

Advantages of Fats Over Polysaccharides:
- Highly Reduced: Fatty acids store more energy per carbon due to higher reduction state.
- Anhydrous: Fats contain less water as they are nonpolar.
- One gram of anhydrous fat stores over six times more energy than one gram of hydrated glycogen.

Short-Term Energy: Supplied by glucose and glycogen for quick delivery.
Long-Term Energy: Supplied by fats for prolonged storage and slower delivery.

Triacylglycerols form lipid droplets in the stomach, where bile acids secreted by the gall bladder act to make lipid droplets more accessible for digestion by lipases.
Lipases, secreted by the pancreas, hydrolyze triacylglycerols into two fatty acids and monoacylglycerol.
The products are carried as micelles to intestinal epithelial cells for absorption.
In the intestine, triacylglycerols are re-synthesized from free fatty acids and monoacylglycerol, forming lipoproteins known as chylomicrons for transport to the bloodstream.

Lipases hydrolyze triacylglycerols into glycerol and fatty acids:
- Glycerol Metabolism: Absorbed by the liver and converted into glycolytic intermediates.
- Fatty Acids: Transported to other tissues for energy.
Certain lipases are regulated by hormones like glucagon and epinephrine, initiating lipolysis.
Glycerol Kinase: Activates glycerol, consuming ATP, but subsequent reactions yield more ATP than the cost incurred, facilitating anaerobic catabolism of fats.

Beta-Oxidation: Occurs in the mitochondria, yielding acetyl-CoA from fatty acids.
Transport Mechanisms:
- Small Fatty Acids: (<12 carbons) cross mitochondrial membranes freely.
- Long-Chain Fatty Acids: Require activation to fatty acyl-CoA via acyl-CoA synthetase on the mitochondrial membrane.
- Fatty acyl-CoA transported via carnation.

Oxidation of acyl-CoA to form trans-Δ2-enoyl CoA and NADH, catalyzed by acyl-CoA dehydrogenase.
Hydration of trans-Δ2-enoyl CoA produces L-3-hydroxyacyl CoA.
Oxidation of L-3-hydroxyacyl CoA generates 3-ketoacyl CoA and NADH.
Cleavage of 3-ketoacyl CoA by thiolase forms acetyl-CoA and a shorter fatty acyl chain (2 carbons shorter).

Stage 1: Conversion of fatty acids into acetyl-CoA via β-oxidation and generation of NADH and FADH2.
Stage 2: Oxidation of acetyl-CoA into CO2 via the citric acid cycle, generating more NADH and FADH2.
Stage 3: ATP production from NADH and FADH2 via the respiratory chain.
- Energy Yield from Complete Oxidation: For a 16-carbon fatty acid like palmitate:
- Oxygen yield: 8 acetyl-CoA x 10 ATP, 7 FADH2 x 1.5 ATP, 7 NADH x 2.5 ATP.
- Total = 108 ATP - 2 ATP (for activation) = 106 ATP.

Cis Double Bonds: Naturally occurring unsaturated fatty acids contain these and are not substrates for enoyl-CoA hydratase.
Additional Enzymes Required:
- Isomerase: Converts cis double bond starting at carbon 3 to a trans double bond at carbon 2.
- Reductase: Reduces cis double bonds elsewhere in the fatty acid chain.
Dietary Fatty Acids: Most are even-numbered, while some sources are odd-numbered (e.g., propionyl-CoA formed from β-oxidation of odd-numbered fatty acids).
- Formation of metaphors (e.g., methylmalonyl CoA) requires a biotin-dependent enzyme.

Acetyl-CoA Entry into Citric Acid Cycle: Requires oxaloacetate.
- Lacking oxaloacetate means acetyl-CoA cannot be converted into glucose.
- Under conditions like diabetes or starvation, when oxaloacetate decreases, acetyl-CoA is diverted to form ketone bodies (e.g., acetoacetate, β-hydroxybutyrate, acetone).
Clinical Relevance: Excess production leads to acidosis due to the moderately strong acidic nature of ketone bodies.
Relationships of metabolic pathways involve:
- Oxaloacetate serving as a precursor for gluconeogenesis.
- Importance of acetyl-CoA in energy metabolism, especially during fasting states.