Lipid Catabolism

Lipid Metabolism

Fatty Acid Synthesis

• Fatty acids are synthesized from acetyl-CoA.

• Acetyl-CoA is produced from the breakdown of glucose and amino acids and oxidized in the citric acid cycle (CAC).

• In a well-fed state, acetyl-CoA is moved from the mitochondria to the cytosol for fatty acid biosynthesis.

• Fatty acids are used to synthesize triacylglycerol (TAG) for storage.

  $\text{Acetyl-CoA} \rightarrow CO_2 + e^- \rightarrow \text{Citric Acid Cycle (CAC)}$
  $\text{Glucose} \rightarrow \text{Pyruvate} \rightarrow \text{Acetyl-CoA}$
  $\text{Protein} \rightarrow \text{Amino Acids (AA)} \rightarrow \text{Acetyl-CoA}$
  $\text{Acetyl-CoA} \rightarrow \text{Fatty Acids (FA)} \rightarrow \text{Triacylglycerol (TAG)}$
  $\text{Diet} \rightarrow \text{Fatty Acids (FA)}$

Tissue-Specific Roles in Lipid Metabolism

• Adipose Tissue: Synthesizes, stores, and mobilizes triacylglycerols. Brown adipose tissue carries out thermogenesis.

• Liver: Processes fats, carbohydrates, and proteins from the diet; synthesizes and distributes lipids, ketone bodies, and glucose for other tissues; converts excess nitrogen to urea.

• Small Intestine: Absorbs nutrients from the diet and moves them into the blood or lymphatic system.

• Portal Vein: Carries nutrients from the intestine to the liver.

• Pancreas: Secretes insulin and glucagon in response to changes in blood glucose concentration.

• Brain: Transports ions to maintain membrane potential; integrates inputs from body and surroundings; sends signals to other organs.

• Cardiac Muscle: Uses ATP generated aerobically to pump blood.

• Skeletal Muscle: Uses ATP generated aerobically or anaerobically to do mechanical work.

• Lymphatic System: Carries lipids from the intestine to the liver.

Lipid Catabolism

• Lipid catabolism involves the breakdown (mobilization) of stored lipids.

• Relevant reading material: Chapter 17.1 (Digestion, Mobilisation and Transport of Fats: pages 601-604).

• Topics include dietary lipids, lipid transport, and lipoprotein lipase.

Intracellular TAG Storage

• Intracellular TAG is stored in lipid droplets found in fungi, plants, insects, and mammalian cells.

• Lipid droplets serve as a metabolic fuel store, aid in membrane expansion, and store sterols.

• They prevent toxicity by free (unesterified) fatty acids and participate in signaling.

• Structure: Phospholipid monolayer surrounding TAG and cholesterol esters.

• Size: Adipocytes contain lipid droplets ranging from 0.1 to 100 µm.

White vs. Brown Adipocytes

• White Adipocytes: Primarily for TAG storage.

• Brown Adipocytes: Contain more mitochondria and are involved in thermogenesis.

Advantages of TAG as an Energy Store

• Fatty acids carry more energy per carbon because they are more reduced compared to polysaccharides.

• Fats require less water for storage because they are nonpolar.

• Glucose and glycogen are for short-term energy needs and quick delivery.

• Fats are for longer-term energy needs, efficient storage, and slower delivery.

Breakdown of TAG Stores by Lipases

• TAG is broken down into fatty acids, diacylglycerol (DAG), monoacylglycerol (MAG), and glycerol by lipases.

  $\text{TAG} \rightarrow \text{FA} + \text{DAG}$
  $\text{DAG} \rightarrow \text{FA} + \text{MAG}$
  $\text{MAG} \rightarrow \text{FA} + \text{Glycerol}$

• Energy Yield:

  • Beta-oxidation of fatty acids: ~95% of energy.

  • Glycerol metabolism: ~5% of energy.

• Glycerol Metabolism:

  • Glycerol can be converted to glycerol-3-phosphate (glycerol-3-P) by glycerol kinase.

  • Glycerol-3-P can be converted to dihydroxyacetone phosphate (DHAP) by G3P dehydrogenase, linking it to glycolysis.

  • DHAP can be converted to glyceraldehyde-3-phosphate by triose phosphate isomerase.

• Key Enzymes:

  • Adipose triglyceride lipase (ATGL).

  • Hormone-sensitive lipase (HSL).

  • Monoacylglycerol lipase (MGL).

Hormonal Regulation of TAG Breakdown

• Hormones (glucagon and adrenaline) trigger the breakdown of stored TAG.

• These hormones bind to receptors (GPCRs), increasing cAMP and activating protein kinase A (PKA).

• PKA phosphorylates HSL (activating it) and perilipin (recruiting HSL).

• TAG stores are broken down under conditions of fasting, starvation, or exercise.

Adipose Triglyceride Lipase (ATGL)

• ATGL is highly expressed in adipose tissue and lower in other tissues.

• Its transcription is inhibited by insulin and induced by fasting.

• ATGL is activated by the regulatory protein CGI-58 and by phosphorylation via AMPK.

Coordinated Regulation of Lipases

• Phosphorylation of perilipin causes dissociation of CGI-58.

• CGI-58 recruits ATGL to the surface of the lipid droplet.

• ATGL breaks down TAG to DAG, amplifying the signal and leading to rapid activation of lipolysis.

• The rate of lipolysis increases 100-fold.

Insulin's Role in Inhibiting TAG Breakdown

• Insulin inhibits HSL, thus inhibiting the breakdown of TAG stores when blood glucose levels rise.

• Insulin also decreases PDE (phosphodiesterase) activity.

Transport of Fatty Acids in the Bloodstream

• Fatty acids released from adipocyte TAG stores are transported in the bloodstream bound to albumin.

• The process involves multiple steps:

  1. Glucagon binds to its receptor, activating adenylyl cyclase.

  2. Adenylyl cyclase converts ATP to cAMP.

  3. cAMP activates PKA.

  4. PKA phosphorylates perilipin and HSL.

  5. CGI-58 interacts with ATGL.

  6. ATGL hydrolyzes triacylglycerol to diacylglycerol.

  7. HSL hydrolyzes diacylglycerol to monoacylglycerol.

  8. MGL hydrolyzes monoacylglycerol to glycerol.

  9. Fatty acids are released from the adipocyte.

  10. Fatty acids enter the blood.

  11. In the myocyte, fatty acids undergo beta-oxidation, enter the citric acid cycle, and fuel the respiratory chain to produce $CO_2$ and ATP.

Summary of TAG Breakdown

• Triacylglycerol is stored in lipid droplets in adipocytes.

• The breakdown of triacylglycerol into fatty acids and glycerol is triggered by hormones.

• ATGL and HSL are activated by glucagon and adrenaline.

Dietary Lipids

• Relevant reading: Chapter 17.1 (Digestion, Mobilisation and Transport of Fats: pages 650-651) and Chapter 21.4 (pages 842-846) from Lehninger.

Processing of Dietary Lipids in Vertebrates

• Fatty acids obtained from dietary fat can account for ≥40% of energy requirements.

• Dietary TAG is taken up by epithelial cells and converted to chylomicrons.

• Chylomicrons are transported to muscle, adipose tissue, etc.

Chylomicrons and Lipoproteins

• Lipoproteins provide a means of transporting hydrophobic lipids between tissues.

• Hydrophobic lipids are in the core, surrounded by phospholipids and specific apolipoproteins.

• Apolipoprotein C-II (ApoC-II) binds to lipoprotein lipase on the surface of capillaries in muscle and adipose tissue.

Lipoprotein Lipase (LPL)

• ApoC-II activates lipoprotein lipase to cause the breakdown of chylomicron TAG.

• LPL is expressed on the surface of capillaries in muscle and adipose tissue.

• LPL hydrolyzes TAG, and the resulting fatty acids enter cells for oxidation or storage.

Function of Lipoprotein Lipase

• LPL is an extracellular lipase activated by binding to apoC-II on lipoproteins.

• Fatty acids released from the breakdown of lipoprotein TAG enter cells for oxidation or storage.

Classes of Lipoproteins

• Chylomicrons:

  • Least dense (most TAG).

  • Transport dietary lipids from the intestine.

  • High concentrations of TAG and cholesteryl esters.

• Very-Low-Density Lipoproteins (VLDL):

  • Transport endogenous lipids from the liver.

• Low-Density Lipoproteins (LDL):

  • Enriched in cholesterol/cholesteryl esters.

  • Produced by the removal of TAG from VLDL.

• High-Density Lipoproteins (HDL):

  • High in protein.

  • Produced from the conversion of LDL and VLDL cholesterol to cholesteryl esters.

Apolipoproteins and Lipoprotein Function

• Apolipoproteins function as signals that target lipoproteins to specific tissues or activate enzymes (e.g., LPL).

Lipoprotein Transport Pathway

• Intestine: Dietary lipid is packaged into chylomicrons.

• Liver: Produces endogenous lipids packaged into VLDL and HDL precursors.

• Extrahepatic Tissues: Chylomicrons and VLDL are processed by lipoprotein lipase in capillaries, releasing free fatty acids.

• HDL: Mediates reverse cholesterol transport.

• LDL: Delivers cholesterol to extrahepatic tissues.

Regulation of Lipoprotein Lipase (LPL)

• LPL in muscle and adipose tissue is inversely regulated.

• Fasted State: Lipoprotein FA is released at muscle cells for oxidation.

• Fed State: Lipoprotein FA is released at adipocytes for storage.

Low-Density Lipoproteins (LDL) and Cholesterol Regulation

Regulation of cholesterol synthesis and transport involves:

• Covalent modification of HMG-CoA reductase by AMPK.

• Transcriptional regulation of the HMG-CoA gene by SREBP.

• Proteolytic degradation of HMG-CoA reductase via insig/gp78.

• Transcriptional regulation of the LDL receptor by SREBP.

Lipoprotein Summary

• Lipids are transported in lipoproteins.

• Chylomicrons transport dietary lipids, VLDLs transport endogenous lipids, and LDLs transport cholesterol.

• Apolipoproteins act as signals to target lipoproteins.

• ApoB-100 binds to the cell surface LDL receptor.

• ApoC-II on chylomicrons and VLDLs binds and activates lipoprotein lipase in capillaries of muscle and adipose tissue.

• Regulation of LPL expression determines where lipoproteins are utilized.