Lipid Metabolism: Fatty Acid Degradation

• Sumo wrestling is a good example of lipid metabolism.

Fatty Acid Basics

• Fatty acids are stored as triacylglycerols (TAG) in adipose tissue.
• Fatty acids are linked to glycerol with ester linkages to form Triacylglycerols.

Fatty Acid Degradation

• Fatty acids in adipose tissue are made accessible in three stages.
• Mobilization involves the degradation of TAG to release fatty acids and glycerol into the blood, triggered by hormones, for transport to energy-requiring tissues.
• Activation activates fatty acids and transports them into the mitochondria to be oxidized.
• Degradation lyses fatty acids to acetyl CoA.

Mobilization Details

• During mobilization, triacylglyceride is broken down by lipase and mixed with 3 molecules of water to form glycerol and fatty acids

Fate of Glycerol and Fatty Acids

• Fatty acids are bound to albumin and transported from fat cells to other tissues.
• Glycerol flows from fat cells to the liver.
• In the liver, glycerol is converted to pyruvate via Glycolysis, and Glucose via Gluconeogenesis.
• In other tissues, fatty acids are converted to Acetyl CoA via fatty acid oxidation.
• Acetyl CoA is incorporated into the CAC (Krebs) cycle and condensed to create CO2 + H2O.

Modification of Fatty Acids

• Upon entering the cell cytoplasm, fatty acids are activated by attachment to CoA via acyl-CoA synthetase.
• This process occurs thanks to pyrophosphatase.

Transportation of Acyl-CoA

• After activation with CoA, fatty acid is transferred to carnitine via carnitine acyltransferase I.
• The result is then transported into the mitochondria by a translocase.
• Inside mitochondria, the acyl group is released as acyl-CoA by carnitine acyltransferase II.
• Carnitine is recovered and exported.

β-oxidation of Fatty Acids

• The four steps in β-oxidation are oxidation, hydration, oxidation, and thiolysis.
• Oxidation of the α & β carbon by acyl-CoA dehydrogenase generates trans-Δ2-enoyl CoA and FADH2.
• Hydration of trans-Δ2-enoyl CoA by enoyl CoA hydratase yields L-3-hydroxyacyl CoA.
• Oxidation of L-3-hydroxyacyl CoA by L-3-hydroxyacyl dehydrogenase generates 3-ketoacyl CoA and NADH.
• Cleavage of the 3-ketoacyl CoA by thiolase forms acetyl CoA and a fatty acid chain two carbons shorter.
• This is similar to TCA steps 6-8.

Fatty Acids With Odd Numbers

• Propionyl CoA will be converted to succinyl CoA to be utilized when fatty acids contain an odd number of carbons
• The process also handles instances where the last acyl-CoA contains 1 carbon or 3 carbons.

Stoichiometry of Fatty Acid Degradation

• Palmitate is a saturated fatty acid with 16 carbons.
• The reaction for one round of β-oxidation involves Cn-acyl CoA, FAD, NAD+, H2O, and CoA, which are converted to Cn-2-acyl CoA, FADH2, NADH, acetyl CoA, and H+.
• The complete reaction for C16 palmitoyl CoA needs 7 runs.
• 8 acetyl CoA, 7 FADH2, and 7 NADH and H+ result from palmitoyl CoA and 7 FAD, 7 NAD+, 7 CoA and 7 H2O.
• ATP production by the ETC: 80 from TCA and 10.5 and 17.5, respectively.
• The total is 108 ATPs.
• However, the activation of fatty acid to consume 2 ATP resulting in is 106

Isomerase

• Isomerase and reductase are used to degrade unsaturated fatty acids
• β-oxidation alone cannot degrade unsaturated fatty acids.
• Odd numbered double bonds require only the isomerase to change the double bond position.
• Even numbered double bonds require both the isomerase and reductase.
• High doeses of trans fat can cause coronary diseases.

Keytones

• Ketone bodies—acetoacetate, 3-hydroxybutyrate, and acetone—are synthesized from acetyl CoA in liver mitochondria.
• They are secreted into the blood for use by tissues like the heart and brain.
• 3-Hydroxybutyrate is formed upon the reduction of acetoacetate.
• Acetone is generated by the spontaneous decarboxylation of acetoacetate.
• 3-hydroxybutyrate is oxidized to acetoacetate in tissues using ketone bodies, which is ultimately metabolized to two molecules of acetyl-CoA.

Synthesis of Ketone Bodies

• 3-ketothiolase, hydroxymethylglutaryl CoA synthase, hydroxymethylglutaryl CoA cleavage enzyme, and D-3-hydroxybutyrate dehydrogenase are all involved in the synthesis of keytone bodies

Degradation of Ketone Bodies

• Liver made them (no CoA transferase).
• The brain and other tissues use them.
• Blood ketone body is acidic.

Keytones and starvation

• Glucose is the major fuel for the brain under normal conditions.
• Proteins are first degraded upon starvation
• After several days of fasting, the brain begins to use ketone bodies as fuel because breaking down fatty acids generates acetyl-CoA, which can't be converted to glucose.
• Ketone body use curtails protein degradation and thus prevents tissue failure.
• Ketone bodies are synthesized from fats, which make it the largest energy store.

Fat conversion

• Fats are converted into acetyl-CoA and processed to the citric acid cycle.
• Oxaloacetate, a citric acid cycle intermediate, is a precursor to glucose.
• However, acetyl-CoA derived from fats cannot lead to the net synthesis of oxaloacetate or glucose due to carbon loss.

Fatty Acid Creation

• Transportation: acetyl CoA is transferred from the mitochondria to cytoplasm.
• Activation: acetyl CoA is activated to form malonyl CoA.
• Condensation: repetitive addition and reduction of two carbon units to synthesize C16 fatty acid (palmitate) on an acyl carrier protein ACP.
• Other fatty acids are converted from palmitate by additional modifications.

Exporting

• Acetyl CoA is exported to the cytoplasm using pyruvate/citrate shuffle.
• The first stage of fatty acid synthesis is transfer of acetyl CoA out of the mitochondria into the cytoplasm,
• Citrate is transported into the cytoplasm and cleaved into oxaloacetate and acetyl CoA.

Gluconeogenesis

• Gluconeogenesis converts pyruvate to oxaloacetate.
• In mitochondria, pyruvate converts to oxaloacetate and oxaloacetate converts to malate.
• Malate, using a malate transporter, is transported to the cytoplasm.
• In cytoplasm, malate is converted to oxaloacetate.

Malonyl CoA Activation

• Acetyl CoA is activated into Malonyl CoA via acetyl CoA carboxylase 1, a biotin-requiring enzyme.

Steps

• Condensation, reduction, dehydration and reduction are required to extend 2 carbons.
• For odd number fatty acid, synthesis starts with propionyl-ACP.
• The coding, reduction, dehydration and reduction are required.

Creation power

• NADPH is required to power the steps of fatty acid synthesis
• Some NADPH can be formed from the oxidation of oxaloacetate, generated from citrate by ATP-citrate lyase.
• NADPH is also provided by the pentose pathway.

Fatty creation vs Lysing

• Synthesis: acetyl CoA to fatty acid condenses C=O to CH2.
• Degradation: fatty acid to acetyl CoA lyses CH2 to C=O.

Stoichiometry of Fatty Acids

• Acetyl CoA + 7 malonyl CoA + 14 NADPH + 7 H+ are converted to palmitate + 7 CO2 + 14 NADP+ + 8 CoA + 6 H₂O for the general the reaction.
• 7 Acetyl CoA + 7 CO2 + 7 ATP are the requirements of synthesis of malonyl CoA from acetyl CoA
• All enzymes are required.
• Fatty acid synthase cannot generate fatty acids longer than C16 palmitate, but Fatty acids are synthesized by enzymes attached to the endoplasmic reticulum.
• Said enzymes extend palmitate by adding two carbon units, using malonyl CoA as a substrate.

Lipid synthesis

• Glycerol is a key ingredient

Phosphatidate Creation

• Phospholipids and triacylglycerol use phosphatidate as their foundation
• Phosphatidate is formed when fatty acids are added to glycerol 3.
• Fatty acid is activated using CoA and then condensed with OH on glycerol.

Creation Steps

• Triacylglycerol synthase is needed, for synthesis from phosphatidate and acyl-CoA.
• It is bound to the endoplasmic reticulum (liver).
• Triacylglycerols are the primary fuel storage in humans.

Phospholipids

• Activated diacylglycerol is required for synthesis.
• Diacylglycerol is activated by forming cytidine diphosphate diacylglycerol (CDP-diacylglycerol).
• CDP-diacylglycerol reacts with an alcohol to form a phospholipid.
• The alcohol is activated by phosphorylation and subsequent reaction with CTP to form CDP-alcohol.
• The activated alcohol reacts with diacylglycerol to form the phospholipid.

Hormones

• Cholesterol is the precursor to steroid hormones

Transporters

• Lipoproteins transport cholesterol and triacylglycerol.
• A core hydrophobic lipid surrounds proteins.
• The particles are categorized according to their densities: chylomicrons, chylomicron remnants, VLDLs, IDLs, LDLs, and HDLs.
• LDLs carry cholesterol in the blood.
• High concentration may lead to heart attack by blocking blood vessels,.
• HDLs are good for returning cholesterol to the liver.