Fatty Acids and Fat Metabolism

Structure of Fatty Acids

• Dietary fats and oils are key components in fat metabolism.

Overview of Fat Metabolism

• Fatty acids are absorbed by cells, where they act as precursors for synthesizing compounds, energy fuels, and substrates for ketone body synthesis.
• Ketone bodies are energy sources which can be transported to other tissues.
• Some cells can synthesize and export fatty acids for storage.

Energy from Fat

• Fats significantly contribute to calorie intake, making up 30-40% of the standard American diet.
• Primarily stored as fat, the body's fuel reserves include 100,000 kcal of fat, 25,000 kcal of protein, and 650 kcal of carbohydrates.
• Fat supplies 60% of the body's energy while resting.
• Stored triacylglycerols can sustain someone through about 30 days of starvation.
• Lipid metabolism oxidizes fatty acids to produce energy or synthesize new lipids from smaller molecules
• It links with carbohydrate metabolism via acetyl CoA, converted from glucose.

Digestion and Absorption of Lipids

• Ingested lipids are 98% triacylglycerols (TAGs).
• Digestion starts in the mouth with aqueous enzymes, having little effect on lipids.
• The stomach physically changes lipids by churning them into droplets called "Chyme".
• Gastric lipase initiates lipid digestion in the stomach, hydrolyzing about 10% of TAGs.
• Intestinal Chyme stimulates cholecystokinin (CCK) release, prompting the gallbladder to release bile, which acts as an emulsifier, breaking down fats.
• Pancreatic lipase (PL) binds to bile-salt micelles to hydrolyze insoluble triglycerides which results in 2 of the 3 fatty acids being released.
• The remaining structure is monoacylglycerol = glycerol and 1 fatty acid.
• Oil droplets form spherical micelles through the help of bile salts and fatty acids.
• Hydrophobic fatty acids and monoacylglycerols accumulate in the micelle's interior.
• Bile salts are located on the exterior.
• Micelles facilitate the transport through the intestinal cell membrane.
• After transport free fatty acids & monoacylglycerols reform into triacylglycerols.
• TAGs combine with proteins to form chylomicrons (lipoproteins).
• Chylomicrons transport TAGs from intestinal cells into the bloodstream via the lymphatic system.
• In the bloodstream, triacylglycerols break down into glycerol and fatty acids for cell absorption.
• Absorbed molecules transform into acetyl CoA for energy or stored as lipids in adipose tissue.

Adipocytes

• Adipocytes, found mostly in the abdominal cavity and subcutaneous tissue, store energy, provide insulation, and act as shock absorbers
• They constantly hydrolyze and resynthesize triacylglycerols

Hormonal Control of Lipolysis

• The breakdown of triglycerides via lipases is hormonally regulated by epinephrine, glucagon, and insulin.
• Epinephrine and glucagon trigger fat breakdown (lipolysis), whereas insulin inhibits it.

Lipolysis

• This process breaks down fats, specifically triglycerides, within adipose tissue.
• Ester bonds must be cleaved via hydrolysis, using water for a chemical reaction.
• The complete process has three steps, each detaching a fatty acid from the glycerol backbone.
• This requires 3 separate enzymes and 3 water molecules:
  • adipose triglyceride lipase breaks the first ester bond leaving a diglyceride.
  • hormone-sensitive lipase facilitates the reaction for the second ester bond forming a monoglyceride.
  • monoglyceride lipase, facilitates the hydrolysis of the middle ester bond producing glycerol (alcohol).
• Adrenaline, Cortisol, and Glucagon stimulate lipolysis while insulin and ketones suppress it.

Fatty Acid Transport

• Fatty acids released from lipolysis are transported via plasma albumin, then transferred to skeletal muscle using the CD36 protein.
• Fatty acids cannot be metabolized for energy in the cytosol and must go to the mitochondria.
• Fat metabolism involves transporting fatty acids from the cytosol through the mitochondrial membranes into the mitochondrial matrix for beta-oxidation and ATP production.
• Short and medium fatty acids freely cross membranes, but longer fatty acids require the carnitine shuttle transport system.
• L-carnitine, a dipeptide, is made in the liver from lysine and methionine for use in the transport system.
• The carnitine shuttle proceeds via:
  • Activation where fatty acids combine with coenzyme A and Acyl-CoA synthetase, producing acyl coenzyme A.
  • Acyl-CoA synthetase enzymes activate fatty acids and are located in the outer mitochondrial membrane.
  • The Acyl group representing the long-chain FA conjugates with carnitine producing Acyl-Carnitine Acyl Carnitine is transported across the inner mitochondrial membrane via carnitine-acylcarnitine translocase, liberating coenzyme A.
• The dislodged coenzyme A returns to activate another fatty acid in the previous step, while the remaining acyl group combines with another coenzyme A within the matrix to reproduce acyl coenzyme A for beta-oxidation.

Beta-Oxidation

• Each beta-oxidation cycle produces one reduced coenzyme FADH2 and one reduced coenzyme NADH at steps 1 and 3.

• These coenzymes link to the electron transport chain, offload electrons and hydrogen, and return as FAD and NAD+ to repeat the cycle.

• High-energy electrons from NADH and FADH2 fuel the electron transport chain, driving ATP production through oxidative phosphorylation.

• Beta-oxidation links to the citric acid cycle through acetyl CoA produced during beta-oxidation which acts as an entry point.

• This process involves cleaving and removing an acetyl group through oxidation.

• Acyl-CoA dehydrogenase catalyzes the first step, removing hydrogens to create FADH2.

• Enoyl-CoA hydratase catalyzes the second step as water is added, producing a secondary alcohol.

• Hydroxyl Acyl CoA dehydrogenase catalyzes the third step where the H is removed from the OH group and is then attached to the beta carbon

• Keto acyl-CoA thiolase catalyzes the fourth and final step where a two-carbon acetyl segment is cleaved away with coenzyme A.

• The remaining fragment combines with S-CoA, forming a six-carbon fatty acyl CoA product which then repeats the cycle.

• In a Fatty Acid:

  • Each acetyl CoA is 10 ATP
  • Each cycle creates 1 FADH2 and 1 NADH
  • For odd numbers one propionyl yields 5 ATP
  • If there is an incomplete cycle (double bond) then there is no FADH2 production
  • Activation costs 2 ATP

Distribution and Metabolism of Glycerol

• One glycerol molecule is formed for each hydrolyzed TAG.
• Glycerol enters the bloodstream and is processed in the liver or kidneys.
• It converts to dihydroxyacetone phosphate in two steps.
• Triacylglycerol lipase, Diacyclglycerol lipase and Monoacylglycerol lipase.
• Only triacylglycerol lipase is activated by epinephrine.
• ATP is used to reduce NAD+ to NADH.
• The primary hydroxyl group is phosphorylated
• Ketones are formed during oxidation.
• Dihydroxyacetone phosphate, an intermediate, connects lipid and carbohydrate metabolism:
  • Through Glycolysis, it converts to Pyruvate, forming Acetyl CoA and releasing energy.
  • Through Gluconeogenesis, it synthesizes Glucose from non-carbohydrate sources.

Ketone Bodies

• A process that requires:
  • Acetyl CoA Acyl Transferase
  • HMG CoA synthase
  • HMG CoA Lyase
  • Beta hydroxyl butyrate dehydrogenase
  • Acetoacetate decarboxylase
  • CoA transferase
  • Thiolase
• This creates:
  • Acetoacetate
  • 3-Hydroxybutyrate
  • Acetone
• They are water soluble, easily transportable, and synthesized in the liver.