Lipids & Lipid Catabolism Flashcards
Lipid Digestion Overview
Digestion Site: Lipids are digested at the lipid-water interface.
Rate Determinant: Digestion rate depends on the surface area of the interface.
Bile Acids: Secreted into the small intestine, increasing surface area through detergent activities.
Role of Bile Acids
Function: Bile acids increase lipid-water surface area.
Mechanism: Detergent activities induce formation of lipid micelles.
Location: Bile acids are secreted into the small intestine for digestion.
Triacylglyceride Degradation
Process: Triacylglycerides broken down by lipases.
Pancreatic Lipase: Catalyzes sequential hydrolysis of triacylglycerols.
Products: Generates free fatty acids and 2-monoglyceride.
Phospholipid Degradation
Pancreatic Phospholipase A2: Degrades phospholipids.
Cleavage: Cleaves C2 fatty acid, yielding lysophospholipids.
Detergent Nature: Lysophospholipids act as detergents, emulsifying fat similar to bile acids.
Lipolysis Process in Adipose Cells
Definition: Lipolysis is the process of releasing fatty acids from triacylglycerols stored in adipose cells.
Regulation: Hormone-dependent, primarily regulated by adrenaline (epinephrine).
Hormone Action: Adrenaline activates G-protein, leading to cyclic AMP (cAMP) production through adenyl cyclase.
Protein Kinase A (PKA) Activation
cAMP Activation: Increasing cAMP levels activate Protein Kinase A (PKA).
PKA Substrates: PKA targets glycogen phosphorylase kinase, perilipin, and hormone-sensitive triacylglycerol lipase.
Perilipin Function: Phosphorylation of perilipin by PKA opens lipid droplets, allowing lipase access.
Lipase Activation
Hormone-Sensitive Lipase (HSL): Activated by PKA phosphorylation.
Triacylglycerol Breakdown: HSL degrades triacylglycerols into fatty acids.
Perilipin Role: Phosphorylation of perilipin facilitates access for lipase to lipid droplet.
Fatty Acid Transport and Utilization
Fatty Acid Release: Fatty acids are released from adipocytes.
Transport: Fatty acids bind to serum albumin in the blood for solubilization and transport.
Target Tissues: Fatty acids enter target tissues via specific transporters for energy production.
Mobilization Trigger
Trigger: Low glucose levels stimulate glucagon release.
Glucagon Action: Binds to adipocyte receptor, activates adenylyl cyclase, and increases cAMP.
PKA Activation: cAMP activates PKA, initiating phosphorylation of lipase and perilipin for triacylglycerol breakdown.
Fatty Acid Activation
Process: Fatty acid activation involves converting fatty acids into fatty-acyl-CoA.
Location: Takes place outside the mitochondria.
Purpose: Preparation for fatty acid degradation to generate energy.
Enzymatic Process
Enzyme: Catalyzed by fatty acyl–CoA synthetase.
Steps: Conjugation of fatty acid with CoA.
Energy Cost: Requires one ATP, yielding AMP and pyrophosphate.
Delta G: Reaction has a positive delta G, overcome by immediate hydrolysis of pyrophosphate.
High Energy CoA Molecules
Product: Formation of high-energy CoA molecules.
Hydrolysis: Immediate hydrolysis of pyrophosphate is crucial.
Net Delta G: Achieves a net negative delta G for the reaction.
Purpose: Provides energy for the subsequent steps in fatty acid metabolism.
Conversion Steps
Catalyst: Fatty acyl–CoA synthetase and inorganic pyrophosphatase catalyze the conversion.
Exergonic Reaction: The overall process is highly exergonic.
Preparation: Converts free fatty acids into activated fatty-acyl-CoA for efficient degradation.
Carnitine Shuttle System
Function: Transports long-chain acyl CoA through mitochondrial membranes.
Conversion: Acyl CoA is converted to acyl carnitine by carnitine acyltransferase I.
Transport: Acyl carnitine travels through the intermembrane space to the inner mitochondrial membrane.
Mitochondrial Entry
Transporter: Specific transporter facilitates the entry of acyl carnitine into the mitochondrial matrix.
Enzyme: Carnitine acyltransferase II converts acyl carnitine back to acyl CoA inside the mitochondria.
Utilization: Acyl CoA is utilized for beta-oxidation, a process in fatty acid metabolism.
Fatty Acid Entry
Process: Fatty acid entry into mitochondria via the acyl-carnitine/carnitine transporter.
Diffusion: Acyl-carnitine moves through the transporter in the inner mitochondrial membrane.
Matrix Reaction: Acyl group is transferred to mitochondrial coenzyme A in the matrix.
Inhibition Mechanism
Inhibition: Acyltransferase I is inhibited by malonyl-CoA.
Prevention: Inhibition prevents simultaneous synthesis and degradation of fatty acids.
Regulation: Malonyl-CoA regulates the balance between fatty acid synthesis and degradation.
Beta-Oxidation Overview
Stage 1: Fatty acid oxidation to acetyl-CoA.
Stage 2: Acetyl-CoA oxidation to CO2 via the citric acid cycle.
Stage 3: Electrons from Stages 1 and 2 drive ATP synthesis in oxidative phosphorylation.
Beta-Oxidation Pathway
Steps: Four-step sequence - Oxidation, Hydration, Oxidation, and Cleavage.
Acetyl-CoA Formation: One acetyl residue is removed as acetyl-CoA from the carboxyl end.
Repetition: Six more passes yield 7 additional acetyl-CoA molecules.
Acetyl-CoA Generation
Total Acetyl-CoA: Eight molecules of acetyl-CoA are formed.
Sequence: Acetyl residues removed from the fatty acyl chain in successive passes.
Carbon Source: The 7th acetyl-CoA arises from the last two carbon atoms of the 16-carbon chain.
Ketone Bodies as Fuels
Utilization: Important fuels for heart, skeletal muscle, kidney cortex, and brain during starvation.
Exclusion: Not utilized by the liver.
Ketone Bodies Overview
Fate of Acetyl-CoA: Besides citric acid cycle oxidation, undergoes ketogenesis in liver mitochondria.
Products: Acetoacetate, -hydroxybutyrate, and acetone are collectively known as ketone bodies.
Properties of Ketone Bodies
Water Solubility: Ketone bodies are water-soluble equivalents of short fatty acids.
Synthesis Location: Synthesized in the mitochondrial matrix.
Acetone in Ketone Bodies
Metabolism: Acetone is not metabolized; it is “blown off” in the lungs.
Conditions: Produced in excess during ketosis, untreated diabetes, or high protein-low carbohydrate diets.
Ketosis and Acidosis
Ketosis Causes: More ketone bodies produced than metabolized, seen in untreated diabetes or specific diets.
Acidosis Risk: Ketone bodies are acidic; high levels, especially in untreated diabetes, can lead to blood acidosis.
Ketone Body Formation Overview
Normal Levels: Ketone body formation is typically low under normal conditions.
Trigger: Increases during acetyl-CoA accumulation, such as in starvation or untreated diabetes
Steps in Ketone Body Formation
Enzymatic Catalysis: Thiolase catalyzes the condensation of two acetyl-CoA molecules.
Intermediates: Formation of acetoacetyl-CoA and then HMG-CoA, the precursor of the three ketone bodies.
Location: Process occurs in the matrix of liver mitochondria.
Reasons for Liver Ketone Body Formation
Oxaloacetate Limitation: Occurs when oxaloacetate is limited due to its utilization in gluconeogenesis.
High NADH Levels: PDC, isocitrate dehydrogenase, and alpha-ketoglutarate DeH are inhibited due to elevated NADH levels during starvation.
Citric Acid Cycle Inhibition
Oxaloacetate Depletion: Limited availability for citric acid cycle due to oxaloacetate being consumed in gluconeogenesis.
Enzyme Shutdown: PDC, isocitrate dehydrogenase, and alpha-ketoglutarate DeH are inhibited under high NADH levels.
Significance of Ketone Bodies in Liver
Alternative Energy Source: During starvation, ketone bodies serve as an alternative energy source when glucose is scarce.
Maintaining Energy Balance: Allows the liver to continue producing energy-efficient ketone bodies when glucose supply is limited.
Storage Lipids
Fatty acids, akin to low oxidation state hydrocarbons, undergo highly exergonic cellular oxidation to CO2 and H2O, resembling burning fossil fuels.
Structural Lipids in Membranes
Biological Membranes: Composed of lipid bilayers forming cell barriers preventing the passage of polar molecules.
Amphipathic Nature: Lipids in bilayers are amphipathic, with hydrophobic fatty acids interacting internally and hydrophilic parts interacting externally and with the cytoplasm.
Diversity: Enormous diversity in membrane lipids due to various combinations of hydrophilic head groups and fatty acids.
Trans Fatty Acids
Purpose: Improve shelf life and stability, commonly used in deep frying and baking.
Sources: Found in partially hydrogenated oils like Crisco and margarine.
Natural Occurrence: Present in low amounts (2-5% of total fat) in milk and meat from ruminants (cows and sheep).
Health Impact: Associated with increased heart disease; FDA banned their use in 2018.
Triacylglycerol
Major Fat Storage Form
Energy Content: More reduced than carbohydrates, containing twice as much energy per gram.
Hydrophobic Nature: Does not require carrying the weight of water (2g water/g carbohydrate) necessary for hydration.
Fluid Mosaic Model for Membrane Structure
Composition: Membranes consist of lipids (phospholipids and cholesterol) and proteins.
Hydrophobic Region: Interior fatty acyl chains form a fluid, hydrophobic region.
Protein Movement: Proteins and lipids can move laterally in the plane of the bilayer, but movement between leaflets is restricted.
Carbohydrate Moieties: Some extracellular proteins have attached carbohydrate moieties.
Sphingolipids
Sphingosine
Ceramide
Sphingomyelin
Glycosphingolipids:
Sphingosine
18C amino alcohol with trans configuration of C4=C5 double bond.
Ceramide
Sphingosine with fatty acid via amide linkage.
Sphingomyelin
Second most common lipid in the plasma membrane; ~85% of all sphingolipids in humans.
Glycosphingolipids
Ceramide with one or more sugar residues; examples include cerebroside and ganglioside.
Lipids as Signaling Molecules
Steroids
Eicosanoids
COX Inhibition
Steroids
Derived from cholesterol; examples include testosterone, estradiol, cortisol, and aldosterone.
Eicosanoids
Produced from arachidonic acid by COX enzymes; includes prostaglandins, thromboxanes, and leukotrienes.
COX Inhibition
Nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin and ibuprofen block the formation of prostaglandins and thromboxanes by inhibiting cyclooxygenase (COX).
Aspirin Mechanism
Acetylation of COX 1 and 2: Aspirin (acetylsalicylic acid) acetylates and inactivates both COX 1 and 2.
Thromboxane Inhibition: Blocks the production of thromboxane, a lipid-based signaling factor.
Platelet Aggregation: Thromboxane increases platelet aggregation, forming clots; aspirin inhibits this, reducing clot formation.
Aspirin and Cardiovascular Disease
Heart Attack and Stroke: Thromboxane increases blood clots, leading to heart attacks and strokes.
Cardiovascular Risk Reduction: Aspirin inhibits thromboxane, decreasing cardiovascular disease risk.
Specific COX2 Inhibitors and Issues
COX1 and COX2 Inhibition
Vioxx Withdrawal:
Prostacyclin and Thromboxane Balance
Need for Selectivity: Specific COX2 inhibitors sought for treating osteoarthritis and pain without stomach bleeding.
COX1 and COX2 Inhibition:
Aspirin and ibuprofen inhibit both COX1 and COX2, protecting the stomach lining but causing bleeding.
Vioxx Withdrawal:
FDA-approved Vioxx withdrawn in 2004 due to increased heart attack and stroke risks; associated with 88,000 to 140,000 cases of serious heart disease.
Prostacyclin and Thromboxane Balance:
Inhibition of COX2 alone reduces prostacyclin production, altering the prostacyclin to thromboxane ratio, increasing cardiovascular disease risk.
