Lipid Metabolism / Ketogenesis

White Adipose Tissue (WAT) Functions (4)

Glucose/lipid metabolism, secretion of usable fatty acids as well as leptin, insulation, and structure

Leptin

A hormone produced by adipose cells that acts as a satiety factor in regulating appetite

Brown Adipose Tissue (BAT) Functions (2)

Thermogenesis and glucose/lipid metabolism

Thermogenesis

Using controlled uncoupled respiration to generate heat in response to lowering body temp

Uncoupling Protein 1 (UCP1)

Uniquely expressed in BAT, this uses long chain FAs to carry protons across the MIM into the matrix. This process is inhibited by diphosphates (GDP/ADP)

There are 3 major stages of fatty acid metabolism while fasting....

Lipolysis, activation, and β-oxidation

Lipolysis

The release of triacylglycerols from storage in WAT. Occurs in the cytoplasm and on the surface of WAT cells. Mediated by lipases and regulated by hormones. Lipases are activated by phosphorylation via PKA. PKA is activated by cAMP when energy charge is low. Glucogon activates, insulin inhibits.

Fatty Acid Activation

Use energy from ATP to form a fatty acyl CoA that increases the FA's water solubility and accessibility to enzymes. Then in order to cross the MIM, it must become fatty acyl carnitine (catalyzed by CAT-1) and once inside the MIM turned back to fatty acyl CoA (catalyzed by CAT-2)

β-Oxidation

This is a spiral of repetitive reactions of ever decreasing substrate size. There are four repeated steps of FAD oxidation (rate limiter) of the β bond creating an a-β double bond, then a water attacks the DB forming a hydroxyl group on the β carbon, then NAD+ oxidizes the hydroxyl into a β-ketone, and then acetyl CoA conducts an acyl transfer and breaks the a-β bond. The β carbon now becomes the ipso carbon and continues down the cascade losing 2 carbons each cycle.

Result of β-oxidation

Acety CoA, NADH, and FADH2 are all generated

Rate-limiting step of β-oxidation

Initial FAD oxidation

Ketogenesis

The generation of ketone bodies that will be used as a source of energy, primarily for the brain

3 main ketone bodies that provide usable energy

Acetoacetate, β-hydroxybutyrate, and Acetone (in order of increasing energy)

Where does ketogenesis occur?

The mitochondrial cells of the liver during starvation

Why does ketogenesis occur?

During starvation, many CAC intermediates are diverted to GNG and not for energy production, but PDH doesn't slow as well as β-oxidation is going on, so there is an excess of acetyl CoA in the body. Since only Acetyl CoA is required for ketogenesis, that's where it goes

What is the only precursor for ketogenesis?

Acetyl CoA as it provides both energy and a carbon skeleton

What is the main organs that consume ketone bodies? (Hint: very important)

The brain and heart (and some skeletal muscles) have CoA transferases that make it possible to utilize ketone bodies for energy

How are the main 3 ketone bodies generated?

Acetoacetate is made by combining two acetyl CoAs (w/ slight modifications) and can either be modified into β-hydroxybutyrate or broken down into acetone

Fatty Acid Synthesis

An anabolic pathway occurring only when energy charge is high

Location of FA synthesis

Occurs only in the cytoplasm of liver cells and adipose tissue cells

FA synthesis precursors

Acetyl CoA as carbon source, ATP for energy input, and NADPH as reducing agent

FA synthesis regulation

FA synthesis starts when citrate is in excess in the matrix b/c energy charge is high and excess NADPH also induces

There are 4 stages of FA synthesis

Stage 1: Transport of Acetyl CoA into cytosol

Stage 2: Activate Acetyl CoA

Stage 3: Start elongating the carbon skeleton

Stage 4: Finish when you have reached desired # of Cs

FA Synth Stage One...

Pyruvate-Citrate shuttle is a one way carrier of acetyl CoA to the cytoplasm as the process is irreversible. Consumes ATP

FA Synth Stage Two...

Acetyl CoA is activated into Maloney CoA which is catalyzed by Acetyl CoA Carboxylase (ACC). This is the commitment step for FA synthesis

FA Synth Stage Three...

Fatty Acid Synthase (FAS) is a large protein complex that catalyzes the synthesis of long chain FAs from acetyl CoA and Malonyl CoA. Within the FAS there is an acyl carrier protein that holds everything in place

FA Synth Stage Four...

Elongation occurs in 4 repeating steps condensation of the malonyl and acetyl CoA, reducing of the ketone to an alcohol, removal of the alcohol to form a DB, and then reducing the DB to an alkane

FA elongation is the reverse of...

β-oxidation

FA Synthesis Regulation

Since stage 2 is the committed step, it is highly regulated mainly by reversible covalent modifications. AMPK phosphorylates ACC, and is deactivated by cAMP when energy charge is low