Fatty Acid Breakdown (Lipolysis)

Fatty Acid Role

Fuel molecules for energy storage

• Breakdowns to yield twice the energy that the breakdown of glucose yields

• Synthesis to store energy

Done to generate ATP and reducing equivalents

Fatty Acid Role

Building blocks for phospholipids and glycolipids

Fatty Acid Role

Anchors for lipoproteins

• One way to target proteins to a membrane location

Fatty Acid Role

Derivatives serve as intracellular messengers and ligands

• Ex. prostaglandins, leukotrienes, aracidonic acid, eicosanoids, specific phospholipid and DAG species

Fatty Acid Degradation Step 1

Oxidation to form double bond

• Molecule is oxidized to form a double bond between carbons 2 and 3 of the esterified product

  • Removal of 2 hydrogen atoms (first oxidation) → double bond forms between α and β carbons

Fatty Acid Degradation Step 2

Hydration → yields an alcohol

• α-β Double bond is hydrated to yield an alcohol at the β-carbon

  • By enoyl-CoA hydratase

Fatty Acid Degradation Step 3

2nd Oxidation → ketone produced

• Newly formed hydroxyl group is oxidized to a ketone

  • By hydroxyacyl CoA dehydrogenase

• NAD+ is the electron acceptor (new NADH can feed into the ETC at complex I)

Fatty Acid Degradation Step 4

Thiolysis — Cleavage between carbons 2 and 3

• Yields activated acetate (acetyl-CoA) and a fatty acid two carbons shorter

  • by Thiolase

Triacylglycerols (TAGs)

Lipids are mainly ingested as this

• NOT water-soluble

• Incorporated into mixed micelles with bile salts so they can be accessed by degradative enzymes

Pancreatic Triacylglycerol Lipases

Catalyze hydrolysis of 2 fatty acid-glycerol ester linkages

• NOT at C2 of the glycerol

Works at lipid-water interface, and requires a co-lipase in a 1:1 ratio

• Binds better when enzyme is in contact with a micelle containing phosphatidycholine and bile salts

Bile Salts

Made in the liver, but stored in the gall bladder

• Ex. glycocholate — synthesized from cholesterol

Chylomicrons

Lipoprotein for blood transport of triglycerides, cholesterol and fat-soluble vitamins that originate from the diet

• Largest and lease dense of the lipoproteins

  • Core of TAGs and cholesterol esters

  • surface of amphipathic molecules like cholesterol, phospholipids and apolipoproteins

Lipoprotein Lipase

Apolipoprotein CII on the chylomicron activates this enzyme (destination tissue)

• Catalyzes hydrolysis of TAGs to fatty acids and monoacylglycerol

• Fatty acids enter cells for use as fuel (muscle) or stored (adipose tissue)

Adipose Tissue

The storage place for TAG until they’re needed

• TAGs are resynthesized, coalesced into fat droplets that grow to occupy almost the entire cell

• Surrounded in phospholipid monolayer containing proteins for triacylglycerol mobilization

Lipid Storage Droplets

TAGs are stored in a single adipocyte within these

• Store TAG an esterified cholesterol and cholesterol derivatives

• Outer layer is a phospholipid layer

Fatty Acid Carbons’ Ultimate Fate

Acetyl-CoA is…

Glucagon and Epinephrine

Mobilization of fatty acids gets stimulated by

Protein Kinase A

cAMP stimulates this to phosphorylate perilipin and hormone-sensitive lipase in active form

Perilipin

Restructures the fat droplets making fatty acids more accessible and releases a coactivator for the first lipase

HS Lipase

Performs the second (DAG) lipase activity

Monoacylglycerol (MAG) Lipase

Performs the final hydrolysis to yield 3 fatty acids and glycerol from a TAG

Chanarin-Dorfman Syndrome

• Coactivator required by ATGL is missing/defective

  • Fats accumulate throughout the body because they cannot be released by ATGL

• Dry skin, enlarged liver, muscle weakness, mild cognitive disability

Albumin Proteins

Free fatty acids are carried through the blood by this

Glyceraldehyde-3-phosphate

Glycerol in the liver converts to this

• Can participate in either glycolysis or gluconeogenesis

Acylcarnitines

The form that long-chain fatty acids take on in order to shuttle to the matrix from the outer mitochondrial membrane

• Fatty acid transesterified from CoA to the hydroxyl group of carnitine

Acyl-CoA Dehydrogenase

FADH₂ prosthetic group strongly binds to this enzyme, making electrons carried by FADH₂ take an interesting path to enter ETC

• E-FAD(H₂) → ETF-FAH(H₂) → Fe-S (ox/red) → Ubiquinol/none

E-FAD/FADH₂

Enzyme-bound

ETF-FAD/FADH₂

Electron transferring flavoprotein

Enoyl-CoA Hydratase

Enzyme that catalyzes the reaction of hydration across the double bond in β-oxidation

Hydroxyacyl CoA Dehydrogenase

Enzyme that catalyzes the reaction where the hydroxyl group formed oxidizes into a ketone in β-oxidation

Thiolase

Enzyme that catalyzes the cleavage of the carbon-carbon bond in β-oxidation

Acyl-CoA Synthetase

Enzyme that catalyzes the reaction for activating the fatty acid

Carnitine Acyltrasnferase

Enzyme that catalyzes the reaction for transporting fatty acids into the mitochondrion

10 ATP

The citric acid cycle yields how much ATP?

• 1 GTP = 1 ATP

• 3 NADH → 3(2.5) = 7.5

• 1 FADH₂ → 1.5

1.5 ATP

Every FADH₂ in complex II is equivalent to how many ATP molecules?

2.5 ATP

Every NADH is equivalent to how many ATP molecules?

106 ATP

How many ATP molecules are generated from the β-oxidation of Palmitoyl-CoA (16-carbon long chain)

Succinyl-CoA

An intermediate of TCA

• Yielded when last round of β-oxidation fatty acid has an odd-number of carbons

• Propionyl-CoA is carboxylated to form 4-C molecule

  • CO-S-CoA moiety is migrated to the methyl substituent to yield this

Ketone Bodies

Acetyl-CoA makes this when nutrients (carbohydrates) are scarce for the brain, heart, and muscle can use as fuel under starvation conditions

• Accumulates because it cannot enter TCA → brain starts to run out of glucose

Oxaloacetate

Acetyl-CoA can only enter if this is present