Metabolic

Lipid metabolic pathways are vital for energy storage, cell structure, and hormone synthesis. Their metabolism is a complex set of processes for both breaking down and building up these molecules

• Key Pathways
  • Lipolysis: Triglyceride breakdown to release fatty acids and glycerol
  • Fatty Acid Oxidation (Beta-Oxidation): Fatty acid breakdown to generate energy
  • Lipogenesis: Fatty acid synthesis from acetyl-CoA
  • Triglyceride Synthesis: Esterification of fatty acids with glycerol to form triglycerides
  • Cholesterol Synthesis: A multi-step process to produce cholesterol
  • Lipoprotein Metabolism: The processes of assembling, transporting, and breaking down lipoproteins to deliver lipids throughout the body

Lipolysis

• Purpose: To break down stored triglycerides (fats) into glycerol and fatty acids
• Location: Cytosol of adipose (fat) tissue cells
• Regulation
  • Hormone-sensitive lipase (HSL) is the rate-limiting enzyme
  • Activated by: Epinephrine, glucagon, cortisol (hormones that signal low energy)
  • Inhibited by: Insulin (hormone that signals high energy)
• Process
  1. Hormone binds to receptor
  2. Signal cascade activates protein kinase A (PKA)
  3. PKA phosphorylates and activates HSL
  4. HSL hydrolyzes triglycerides into diglycerides, monoglycerides, and ultimately glycerol and fatty acids
• Fate of Products
  • Fatty acids bind to albumin in the blood and are transported to tissues for energy use (beta-oxidation)
  • Glycerol is transported to the liver for gluconeogenesis or glycolysis

Fatty Acid Oxidation (Beta-Oxidation)

• Purpose: To break down fatty acids into acetyl-CoA for energy production (primarily in mitochondria)
• Location: Mitochondrial matrix
• Process
  1. Activation: Fatty acid is activated by coenzyme A (CoA) to form fatty acyl-CoA
     • Requires ATP
  2. Transport: Fatty acyl-CoA is transported into the mitochondrial matrix via the carnitine shuttle
  3. Beta-Oxidation Cycle
     • Each cycle shortens the fatty acyl-CoA by two carbon atoms, producing:
       • One molecule of acetyl-CoA (enters Krebs Cycle)
       • One molecule of FADH2 (enters electron transport chain)
       • One molecule of NADH (enters electron transport chain)
• Regulation
  • Carnitine palmitoyltransferase I (CPT-I) is the rate-limiting enzyme
  • Inhibited by: Malonyl-CoA (product of fatty acid synthesis)
• Energy Yield: Very efficient energy production
  • Example: Palmitic acid (16 carbons) yields 129 ATP
• Odd-Chain Fatty Acids
  • Oxidation proceeds normally until the last three carbons
  • Propionyl-CoA is formed, which is converted to succinyl-CoA (enters Krebs Cycle)

Ketogenesis

• Purpose: To produce ketone bodies (acetone, acetoacetate, beta-hydroxybutyrate) from acetyl-CoA during periods of prolonged fasting, starvation, or uncontrolled diabetes
• Location: Mitochondrial matrix of liver cells
• Process
  1. Acetyl-CoA molecules combine to form acetoacetyl-CoA
  2. Acetoacetyl-CoA is converted to HMG-CoA
  3. HMG-CoA is cleaved to form acetoacetate
  4. Acetoacetate can be:
     • Reduced to beta-hydroxybutyrate
     • Spontaneously decarboxylated to acetone
• Regulation
  • Availability of fatty acids and acetyl-CoA
• Fate of Ketone Bodies
  • Released into the blood and transported to other tissues (brain, heart, muscle) for energy use
  • Converted back to acetyl-CoA for entry into Krebs Cycle
• Clinical Significance
  • Ketone bodies provide an alternative fuel source for the brain during starvation
  • Excessive production of ketone bodies can lead to ketoacidosis (dangerous lowering of blood pH), especially in uncontrolled diabetes

Lipogenesis

• Purpose: To synthesize fatty acids from acetyl-CoA
• Location: Cytosol of liver and adipose tissue cells
• Process
  1. Acetyl-CoA Transport: Acetyl-CoA is transported from the mitochondria to the cytosol via the citrate shuttle
  2. Activation: Acetyl-CoA is carboxylated to form malonyl-CoA by acetyl-CoA carboxylase (ACC)
     • Requires ATP and biotin
  3. Fatty Acid Synthesis
     • Malonyl-CoA and acetyl-CoA are repeatedly added to a growing fatty acid chain by fatty acid synthase (FAS)
     • Requires NADPH
     • Palmitic acid (16 carbons) is the primary product
• Regulation
  • Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme
  • Activated by: Insulin, citrate
  • Inhibited by: Glucagon, palmitoyl-CoA (feedback inhibition)

Triglyceride Synthesis

• Purpose: To synthesize triglycerides (triacylglycerols) from glycerol and fatty acids for storage
• Location: Cytosol of liver and adipose tissue cells
• Process
  1. Glycerol-3-phosphate is formed from either:
     • Glycerol (in the liver)
     • Dihydroxyacetone phosphate (DHAP) from glycolysis (in adipose tissue)
  2. Fatty acids are activated by CoA to form fatty acyl-CoA
  3. Fatty acyl-CoA molecules are sequentially added to glycerol-3-phosphate to form:
     • Lysophosphatidic acid
     • Phosphatidic acid
     • Diacylglycerol
     • Triacylglycerol (triglyceride)
• Regulation
  • Availability of glycerol-3-phosphate and fatty acids
  • Insulin promotes triglyceride synthesis

Cholesterol Synthesis

• Purpose: To synthesize cholesterol, an essential component of cell membranes and precursor for steroid hormones and bile acids
• Location: Cytosol and endoplasmic reticulum of liver cells
• Process: A complex, multi-step pathway involving:
  1. Acetyl-CoA molecules combine to form HMG-CoA
  2. HMG-CoA is reduced to mevalonate by HMG-CoA reductase (the rate-limiting enzyme)
  3. Mevalonate is converted to isopentenyl pyrophosphate
  4. Isopentenyl pyrophosphate is converted to squalene
  5. Squalene is cyclized and modified to form cholesterol
• Regulation
  • HMG-CoA reductase is the rate-limiting enzyme
  • Inhibited by: Cholesterol, statin drugs
  • Activated by: Insulin
• Fate of Cholesterol
  • Incorporated into cell membranes
  • Used to synthesize steroid hormones (cortisol, aldosterone, sex hormones)
  • Converted to bile acids in the liver (for fat digestion)
  • Packaged into lipoproteins for transport in the blood

Lipoprotein Metabolism

• Purpose: To transport lipids (triglycerides, cholesterol) in the blood
• Lipoprotein Classes
  • Chylomicrons: Transport dietary triglycerides from the intestine to tissues
  • VLDL (Very-Low-Density Lipoproteins): Transport triglycerides from the liver to tissues
  • LDL (Low-Density Lipoproteins): Transport cholesterol from the liver to tissues
  • HDL (High-Density Lipoproteins): Transport cholesterol from tissues back to the liver
• Process
  1. Assembly: Lipoproteins are assembled in the intestine (chylomicrons) or liver (VLDL, HDL)
  2. Secretion: Lipoproteins are secreted into the blood
  3. Lipolysis: Triglycerides in chylomicrons and VLDL are hydrolyzed by lipoprotein lipase (LPL) in capillaries, releasing fatty acids for uptake by tissues
  4. Remnant Uptake: Chylomicron remnants and IDL (intermediate-density lipoproteins) are taken up by the liver
  5. LDL Formation: VLDL is converted to LDL as triglycerides are removed
  6. Receptor-Mediated Uptake: LDL is taken up by cells via LDL receptors
  7. Reverse Cholesterol Transport: HDL picks up cholesterol from tissues and transports it back to the liver for excretion
• Regulation
  • Complex hormonal and enzymatic regulation

Key Terms

• Lipolysis: The breakdown of triglycerides into glycerol and fatty acids
• Beta-Oxidation: The breakdown of fatty acids into acetyl-CoA
• Ketogenesis: The production of ketone bodies from acetyl-CoA
• Lipogenesis: The synthesis of fatty acids from acetyl-CoA
• Triglyceride Synthesis: The formation of triglycerides from glycerol and fatty acids
• Cholesterol Synthesis: The production of cholesterol from acetyl-CoA
• Lipoproteins: Particles that transport lipids in the blood
• Hormone-Sensitive Lipase (HSL): An enzyme that hydrolyzes triglycerides
• Acetyl-CoA Carboxylase (ACC): An enzyme that carboxylates acetyl-CoA to form malonyl-CoA
• HMG-CoA Reductase: The rate-limiting enzyme in cholesterol synthesis