Lipid Metabolism

Lipid Metabolism

• Diagrams and pictures used in the presentation are for teaching purposes only.
• The topic is Lipid Metabolism.

Lecture Learning Outcomes/Outline

• Students should be able to identify/describe:
  • Structure and Role of Lipids - Main classes of lipid, fatty acids: nomenclature and structure (revision)
  • Fatty Acid Biosynthesis - Biosynthesis of saturated fatty acids, elongation of fatty acids, unsaturation of fatty acids & essential fatty acids, regulation of fatty acid synthesis
  • Acylglycerol Metabolism and Mobilization of Lipids - Biosynthesis and hydrolysis of triacylglycerol, glycerophospholipids: biosynthesis and hydrolysis, acylglycerols as energy source for the body, mobilization of adipose tissue lipids
  • Fatty Acid Oxidation and Ketone Bodies - Outline of fatty acid oxidation (β-oxidation) including stoichiometry & regulation, odd carbon fatty acid and unsaturated fatty acid oxidation, regulation of beta oxidation, ketone bodies: synthesis and utilization
  • Cholesterol biosynthesis - overview of cholesterol biosynthesis, bile and steroid synthesis

Lipids

• Generally all lipids are associated, either or actually, to fatty acids.
• Soluble in non-polar solvents and insoluble in polar solvents.
• Lipids are not polymers.

Classification of Lipids

• Simple Lipids:
  • Neutral fats (triacylglycerols)
  • Waxes
  • Cholesterol esters
• Compound Lipids:
  • Phospholipids
  • Glycolipids
  • Sulpholipids
  • Lipoproteins
  • Aminolipids (proteolipids)
• Derived Lipids:
  • Fatty acids
  • Monoacylglycerol
  • Diacylglycerol
  • Glycerol
  • Cholesterol
  • Steroids (Vitamins A, D, E, K)
  • Aliphatic Hydrocarbons
  • Carotenoids
  • Squalene
  • Vitamins E and K

Fatty Acids

• Saturated fatty acid example: Octanoic Acid
• Unsaturated fatty acid example: 3-Octenoic Acid, 3,6-Octadienoic Acid, and short-hand notations.
• Cis and trans fatty acids - examples of Cis 9-Octadecenoic acid (oleic), Trans 9 - Octadecenoic Acid (elaidic acid)
• Types of fatty acids (according to the number of double bonds): Saturated, Monounsaturated, Polyunsaturated.
• Naturally occurring fatty acids - examples: Cis form, Not conjugated, Even numbered, Linoleic Acid 18:2 Δ9, Δ12, Linolenic Acid 18:3 Δ9, Δ12, Δ15.

Fatty Acid Composition of Fats of Animal and Plant Origin

• Data showing the composition of saturated, monounsaturated, and polyunsaturated fatty acids in various animal and plant fats.

Melting Points and Solubility in Water of Fatty Acids

• Melting point increases with increasing chain length
• Solubility in water decreases with increasing chain length
• Melting point of fatty acids decreases with increasing number of double bonds

Effects of Double Bonds on the Melting Points

• The melting point decreases with increasing number of double bonds.

Fat and Oils

• Information on glycerol, fatty acids, and triglycerides.

Fat from Diet & Adipose Cells

• Triglycerides are the major form of stored energy in the body.
• Insulin mediates/stimulates storage of fatty acids in the form of triglycerides.
• Hormones (glucagon, epinephrine, ACTH) trigger release of fatty acids from adipose tissue.

Fatty Acid Metabolism

• Diagram illustrating fatty acid metabolism, including lipogenesis, lipolysis, β-oxidation, ketogenesis, and the TCA/Krebs cycle.
• Synthesis of fatty acids occurs in the cytosol.

Source of Acetyl CoA for Fatty Acid Synthesis

• Glucose → pyruvate → Acetyl CoA
• Important reactions: Acetyl-CoA carboxylase, Fatty acid synthase

Acetyl-CoA Carboxylase

• Irreversible two-step reaction
• Animal cells - one multifunctional polypeptide
• Biotin carboxylase
• Biotin carrier protein
• Transcarboxylase
• Requires a biotin prosthetic group

Fatty Acid Synthesis Requires NADPH

• Information on how Fatty acid synthesis requires NADPH.

Initiation of Fatty Acid Synthesis

• Acetyl CoA is first added to ACP, then transferred to β-Ketoacyl-ACP synthase (KS).
• Similar process as for the growing fatty acid chain after completion of each cycle.
• Then Malonyl-CoA is added to ACP.

Elongation Cycle of Fatty Acid Biosynthesis

• Malonyl-ACP condensation
• β-reduction
• Dehydration
• Enoyl reduction

The Total Reaction

• First Round: 4 carbons long (butyryl)
• Second Round: 6 carbons long
• Third Round: 8 carbons long etc....
• Total of seven rounds to make the product, which is recognized and released by palmitate thioesterase.

Regulation of Fatty Acid Synthesis

• Allosteric regulation (Citrate, Acetyl-CoA, Long chain FAs, inhibits carnitine acyltransferase I).
• Hormonal regulation of Acetyl CoA Carboxylase (Insulin, Glucagon).

Biosynthesis of TAGs and Phospholipids

• Two pathways for glycerol-3-phosphate
• Overview of the steps for TAG biosynthesis
• Pathways branch to TAG or phospholipids
• Regulation of TAG Biosynthesis (Insulin and glucagon).

Biosynthesis of Glycerophospholipids

• Diagram of Glycerophospholipid synthesis.
• Includes various enzymes and intermediates in the process.

Phospholipid Hydrolysis

• Phospholipase A₁, A₂, C, and D.

Lipid-based Hormone Biosynthesis

• Involvement of phospholipids in hormone synthesis.

Triacylglycerol Hydrolysis

• Overview of the steps in triacylglycerol hydrolysis (TG + 3H₂O → Glycerol + 3 Fatty Acid + 3H⁺).
• Involves enzyme lipase.
• Glycerol and fatty acids are used in other processes.

The Utilization of Fatty Acids as Fuel

• The lipids are mobilized from the fat depots (adipose).
• Triglycerides are degraded to fatty acids and glycerols, then transported to energy requiring tissues.
• At these tissues, fatty acids must be activated and transported into mitochondria
• Fatty acids are broken down into Acetyl CoA.

Oxidation of Fatty Acids

• α-oxidation - oxidation of branched fatty acids.
• β-oxidation - Common oxidation.
• w-oxidation - Alternate pathway.

Peroxisomal β-Oxidation

• Peroxisomes - organelles that carry out flavin-dependent oxidations.
• Electrons go to O₂ rather than e- transport chain.

Odd-carbon Fatty Acid Oxidation

• Odd-carbon fatty acids are metabolized normally, until the propionyl-CoA fragment.
• Three reactions convert propionyl-CoA to succinyl-CoA.
• Succinyl-CoA cannot directly enter Krebs cycle and is converted to malate then pyruvate and finally acetyl-CoA.

CoA Activates Fatty Acids for Oxidation

• Acyl-CoA synthetase condenses fatty acids with CoA, with simultaneous hydrolysis of ATP to AMP and PP₁.
• Formation of a CoA ester is expensive energetically.
• Reaction just barely breaks even with ATP hydrolysis.
• Subsequent hydrolysis of PP drives the reaction strongly forward.
• Activated fatty acyl CoA is transported into the mitochondria.

B-Oxidation

• Overall reaction for the B-oxidation of palmitate.
• Stoichiometry of palmitate oxidation.

Regulation of Fatty Acid Oxidation

• Oxidation of fatty acids occurs when energy levels are low.
• Enzymes of β-oxidation are regulated by Malonyl-CoA, carnitine acyltransferase I, (regulated by NADH, and acetyl-CoA thiolase).

Impaired Fatty Acid Oxidation

• Symptoms - carnitine palmitoyltransferase I & II deficiencies and diseases (preterm infants with inadequate biosynthesis or renal leakage, losses during haemodialysis), leading to increased plasma free fatty acids, lipid accumulation in muscles, muscle weakness, ketoacidosis, sudden infant death syndrome (SIDS), imbalance in glucose and fatty acid oxydation.

Ketone Bodies

• Ketone bodies (acetone, acetoacetate, and β-hydroxybutyrate) are synthesized in the liver.
• Major energy source for brain during starvation.
• Source of fuel for brain, heart, and muscle.
• Synthesis pathway - several steps starting from Acetyl-CoA
• Importance and utilization of acetoacetate
• Relation to diabetes

Cholesterol Biosynthesis

• Steps in cholesterol synthesis
• Key enzymes (HMG-CoA synthase; HMG-CoA reductase)
• Feedback regulation of HMG-CoA reductase.
• Cholesterol's roles in bile acid syntheses and steroid synthesis
• The amount produced rather from diet itself
• Cholesterol's roles in bile acid synthesizes.
• Biosynthesis, rather than diet, contributes the majority of body cholesterol, which can deposit in artery walls.
• Statin drugs can be used to curtail synthesis, whereas intake of unsaturated fatty acids improves cholesterol clearance.
• Note: Cholesterol is only excreted from the body in the form of bile.

Bile Acid Synthesis

• Cholesterol → Bile Acids (Several steps).

Steroid Hormone Synthesis in Adrenal Cortex

• Cholesterol is a precursor to steroid hormones and the steps involved in their synthesis in the Adrenal cortex.