Fatty Acid Breakdown

How are fatty acids stored?

• fatty acids are converted to TAGs

• TAGS are stored in adipose tissue

• very little of TAG stored in liver

  • usually exported from liver

  • packaged w/ cholesterol esters and phospholipids

    • different lipoprotein particles

What are lipoproteins?

• macromolecular aggregates made of:

  • core of nonpolar lipids

  • monolayer of phospholipids

  • apolipoproteins

• solubilize and transport lipids in the blood

LDL is ___ cholesterol

bad

HDL is ___ cholesterol

good

Describe fatty acid transport into the mitochondria

• fats are degraded into FAs and glycerol in the cytoplasm of adipocytes

• fatty acids are transported to other tissues for fuel thru blood

• beta oxidation of fatty acids occurs in mitochondria

T/F: large fatty acids diffuse freely across mitochondrial membranes

FALSE

• small fatty acids can freely diffuse

• large fatty acids are transported via acyl-carnitine/carnitine transporter

Describe the catabolism of lipids

• hydrolysis of TAG catalyzed first by hormone-sensitive lipase

  • hydrolysis releases free fatty acids

What is the role of hormone-sensitive lipase (HSL)?

1. low insulin = high E

2. E binds to receptor

   • activates adenylyl cyclase → rise in cellular cAMP levels

3. cAMP activates protein kinase

4. active protein kinase phosphorylates HSL

   • phosphorylated HSL → active

   • dephosphorylated HSL→ inactive

5. activated HSL → hydrolysis on TAGs

   • produced FREE FAs

To enter the matrix, fatty acids need to be in the _____ form

acyl CoA

Stage 1 of FA oxidation

• oxidative conversation of 2-carbon units into acetyl-CoA via beta oxidation w/ concomitant generation of NADH and FADH

  • involves oxidation of beta carbon to thioester of fatty acyl-CoA

Stage 2 of FA oxidation

• oxidation of acetyl-CoA into CO2 via TCA cycle

  • generation of GTP, NADH, and FADH2

Stage 3 of FA oxidation

• generates ATP from NADH and FADH2 via the ETC

What is the beta oxidation pathway?

• each pass (4-step sequence) removes one acetyl group (2C) in the form of acetyl CoA

• repeated passes produces more acetyl CoA

• acetyl-CoA enters the TCA cycle to produce energy

Describe step 1 of beta oxidation: Dehydrogenation of alkane - OXIDATION

• oxidation

• enzyme: acyl-CoA dehydrogenase (AD)

• product: trans-delta²-enoyl-CoA

• e-’s from bound FAD transferred directly to the ETC via electron-transferring flavoprotein (ETF)

Step 1 is analogous to what reaction in the TCA?

succinate dehydrogenase rxn

Describe step 2 of beta oxidation: Dehydrogenation of alkane - RE-HYDRATION

• enzyme: enoyl-CoA hydratase

• product: beta-hydroxyacyl-CoA

• hydrolysis of alkene

• addition of water → alcohol

Step 2 is analogous to what reaction in the TCA?

fumarase rxn

Describe step 3 of beta oxidation

• oxidation

• enzyme: beta-hydroxyacyl CoA dehydrogenase

  • uses NAD redox cofactor as the hydride acceptor

  • e-’s are transferred to the ETC

Step 3 is analogous to what reaction of the TCA cycle?

malate dehydrogenase rxn

Describe step 4 of beta oxidation

• enzyme: acyl-CoA acetyltransferase (aka thiolase)

• ketone carbon in beta-ketoacyl-CoA is electrophilic

• thiol in CoA-SH acts as a nuc and attacks the ketone carbon

  • releases one molecule of acetyl-CoA

• net reaction is thiolysis of C-C bond

  • shortened by 2 C atoms

  • Palmitic acid (C16) → myristic acid (C14)

Catabolic reactions of FAs result in ___ ____

energy release

where does beta oxidation occur?

mitochondrial matrix

What is the ultimate outcome of beta oxidation?

shortening of fatty acid chain, 2C units a time

T/F: At the end of beta oxidation, 2-C units are released as Acetyl CoA

true

Describe the fatty acid catabolism for palmitic acid (C16)

• repeating previous 4 step process six more times (7 TOTAL)

• FADH2 is formed in each cycle (7 TOTAL)

• NADH is formed in each cycle (7 TOTAL)

• last step → 2 molecules of acetyl CoA from acetoacyl CoA

What is ketogenesis?

• synthesis of ketone bodies

• during fasting state: liver has elevated levels of FA

• liver produces acetyl-CoA by fatty acid breakdown via beta oxidation

• elevated acetyl CoA levels cause upregulation of pyruvate carboxylase

  • pyruvate → OAA (gluconeogenesis)

• acetyl CoA enters ketogenic pathway

  • this protects OAA from entering gluconeogenesis

Describe the role of Ketone bodies

• entry of acetyl-CoA into TCA requires OAA

• when OAA is depleted, acetyl-CoA is converted into ketone bodies

  • occurs when there is low carb intake/diabetes

What are the 3 forms that ketone bodies can leave the liver in, which can be delivered by the blood to various tissues?

• acetone

• acetoacetate

• beta-hydroxybutyrate

What parts of the body can use ketone bodies as a fuel source?

• cardiac muscle

• skeletal muscle

• renal cortex

• brain

Describe the generation of free CoA in ketogenesis

1. reverse of last step of beta oxidation

   • acetoacetyl CoA (4C) produced from 2 molecules of acetyl CoA (2C)

     • enzyme: thiolase

2. 3rd molecule of acetyl-CoA is incorporated

   • HMG CoA (6C) is produced

     • enzyme: HMG CoA synthase

Describe the degradation of HMG-CoA in ketogenesis

3. HMG CoA is broken down by HMG CoA lyase to produce the ketone bodies

   • acetone, acetoacetate, and beta-hydroxybutyrate enter blood

     • acetone is exhaled (via pulmonary exhange)

     • acetoacetate and beta-hydroxybutyrate can move to the brain for use in energy production

Describe how ketone bodies are used as fuel

• D-beta-hydroxybutyrate reaches other tissues → produces acetyl CoA in 3 steps

  1. oxidized to acetoacetate by beta-hydroxybutyrate dehydrogenase

  2. thioester formation w/ CoA using beta-ketoacyl CoA transferase

  3. breakdown of acetoacetyl CoA by thiolase

Which hormones stimulate the mobilization/release of fatty acids from adipose tissue to meet energy demands?

glucagon and E

Which reaction in the β-oxidation pathway yields FADH₂?

oxidation of acyl CoA

Which reaction in the β-oxidation pathway yields NADH?

oxidation of 3-hydroxyacyl CoA

Which enzyme catalyzes the cleavage of 3-ketoacyl CoA in fatty acid oxidation?

beta-ketothiolase

Which enzyme catalyzes the formation of 3-ketoacyl CoA in the β-oxidation pathway?

3-hydroxyacyl CoA dehydrogenase

Which reaction product is formed from trans-Δ²-enoyl CoA by 3-hydroxybutyryl-CoA dehydratase?

3-hydroxyacyl CoA

How many energy-rich molecules are formed after b-oxidation of butyryl CoA (C4-acid)?

FADH₂ + NADH + 2 acetyl CoA