ADVANCED NUTRITION MACRONUTRIENTS: CATABOLIC REACTIONS

Catabolism

breaking down molecules into constituent parts that yield ATP

• Lipolysis of TGs within CMs, VLDL by LPL

• Tissue lipolysis of lipid droplets – tissue lipases

• Fatty acid oxidation

• Ketone body utilization in muscle and brain

ApoCII

Recognizes this in circulating lipoproteins that hydrolyzes TG to FFA and glycerol

glycerol kinase

Glycerol goes to liver – used for TG – can be used for TG re-esterification

Lipoprotein Lipase

bound to endothelial cell wall with polysaccharides- faces capillary lumen to hydrolyze TF to Free Fatty Acids and glycerol

peripheral cells

Where can free fatty acids be taken up by?

acyl-CoA synthase

Can convert FFA to acyl-CoA

Triglycerides

What is FFA re-esterified to by GPAT pathway

fed state

What state is GPAT/fed pathway predominant in?

oxidized for ATP or used for storage

What happens to free fatty acids in muscle tissue?

Fasted state

What is state in muscle is FFA oxidation predominant in?

IMTG (Intramuscular Triglycerides)

under overfeeding conditions

Lipolysis

release of FFA from stored lipid droplets

ATGL

adipocyte triacylglycerol lipase (also found in other tissues) that breaks down Triglycerides to Diacylglycerides

HSL

Hormone sensitive lipase – more active on DAG substrate (breaks from Diacylglyceride to monoacylglyceride)

MGL

Monoacylglycerol lipase - high activity - prevents re-esterification of MAG to DAG except in enterocyte

Adipocyte

Where does lipolysis mainly occur in?

fate of liberated fatty acids is beta-oxidation (requires CoA) or transport to other tissues bound to albumin or liver ketone synthesis

What is the fate of lipolysis after?

lipid synthesis is promoted. lipolysis is inhibited

In a fed state with high insulin, what is being promoted? inhibited?

on surface of LD (lipid droplet)

Where will ATGL site be with high insulin?

Perpillins

coat lipid droplet and sequester CGI-58 away from ATGL

CGI-58

Inactive in fed state but required for colipase for the hydrolysis of TG

HSL

an inactive state in the cytosol

where lipolysis (catabolism) is promoted. where lipid synthesis (anabolism) is inhibited.

In a fasted state with high glucagon, what is being promoted? inhibited?

1) Glucagon (epinephrine) activates PKA by generating CAMP via adenyly) cyclase

2) PKA phosphorylates perillpins and HSL

3) C61-58 is released from perillipins- > translocates to ATGL and activates it; ATOL hydrolyzes TG to form DAG

4) phosphorylated HSL translocates from cytosol to perillipins to hydrolyze DAG

5) MGL hydrolyzes MAG to FFA & glycerol - MGL is NOT highly regulated

Steps of activating lipolysis

Protein Kinase A

What is activated by glucagon through generating cAMP?

perillpins and HSL

What does PKA phosphorylate in lipolysis

CGI-58

What is released from perpillins and translocates to ATGL and activates it; ATGL hydrolyzes TG to form DAG

DAG

What is hydrolyzed by HSL translocates from cytosol to perillipins

MGL

hydrolyzes MAG to FFA & glycerol and is not highly regulated

Fatty acid oxidation

happens when there is an addition of COA by acyl-CoA Synthase (ACS)

- Energetic cost is equivalent to 2 ATP = 1st needed for acyl -AMP intermediate ; and needed for regeneration of ADP from AMP

Fatty Acid Synthesis

condensation-> reduction-> dehydration-> reduction

Beta-Oxidation

Dehydrogenation (oxidation) , hydration , Dehydrogenation, cleavage

4 distinct enzymes in mitochondria

How many enzymes does fatty acid oxidation have?

2C

What type of Carbons are oxidized at a time in fatty acid oxidation

1st step of fatty acid oxidation

Get Fatty acyl-CoA into mitochondria via carnitine shuttle with other 4 major steps of beta-oxidation

1) Dehydrogenation

2) Hydration

3) Dehydrogenation

4) Thiolytic Cleavage

carnitine shuttle

Get Fatty acyl-CoA into mitochondria to transport (no fatty acid shorter than 12C does not require carnitine shuttle for mitochondria import)

Thiolase

Enzyme involved in Thiol cleavage

3-L-hydroacyl-CoA dehydrogenase

Enzyme involved in dehydrogenation from L-3-Hydroxylacyl-CoA to 3-Ketoacyl

Enoyl- CoA transferase

Enzyme involved in hydration

Acyl-CoA dehydrogenase

Enzyme involved in dehydrogenation with C₁₆ Acyl-CoA to trans delta 2 Enoyl CoA

Carnitine-acylcarnitine translocase (CACT)

a vital transport protein located in the inner mitochondrial membrane. . It plays a central role in the carnitine shuttle system, which moves long-chain fatty acids into the mitochondria so they can be broken down for energy.

2

FADH₂ transfer electrons to complex II of ETC to power ATP synthase to generate how many moles of ATP per mole of FADH₂

3 moles

NADH transfer electrons to complex of ETC to power ATP synthase to generate how many moles of ATP per mole of NADH

129 ATP

What is the ATP yield for 7 cycles of beta oxidation?

7

How many cycles does beta oxidation have in FAO?

VLCAD

C14-C20 with dehydrogenase for FAs of different lengths

LCAD

C10-C16 with dehydrogenase for FAs of different lengths

MCAD

C6-C12 with dehydrogenase for FAs of different lengths

high concentrations of acetyl-CoA

How is FAO inhibited?

fatty acid availability in mitochondria (as long as adequate NAD/COA are avaliable) & nuclear receptors such as PPARa

How is FAO regulated?

AMPK

CPT-1 regulated by?

Mitochondrial tri-functional protein

contains 3 distinct enzymes that functions as I large protein

AMPK increases will decrease ACC, Malonyl CoA and fatty acid synthesis but increase CPT-I and beta oxidation

In fasted state, what is increased?

AMPK decreases will increase ACC, Malonyl CoA and fatty acid synthesis but decrease CPT-I and beta oxidation

In fed state, what is decreased?

Metformin/Thiazolilidinedione

activate AMPK by ↑ AMP: ATP ratio

AMPK

Activated by phosphorylation by inactivated by dephosphorylation and promotes lipid oxdiation

malonyl-CoA

Acts as an inhibitor to beta oxidation (inhibits carnitine acyl transferase)

Carnitine

dietary or de novo in liver and kidney – diet sources animal products, especially meat

HMG-CoA synthase

only in liver

• Forms acetoacetyl-CoA to HMG-CoA

Liver Mitochondria

Where is Ketone Body synthesis done?

acetoacetyl-CoA

In a condensation of two acetyl-CoA what does it form in ketone body synthesis?

acetoacetate

Loss of 2 acetyl-CoA forms what in ketone body synthesis?

acetone (fruity smell) and 3-HB – acetone is a minor ketone

Two molecules that Acetoacetate can form (ketones?)

3-hydroxybutyrate dehydrogenase

Forms 3-HB from Acetoacetate

spontaneously

How is acetone formed?

plasma ketone. absence of SCOT

Where are ketone bodies oxidized in proportion to? Why is it not oxidized in liver?

during prolonged starvation, very low CHO diet

When are ketone bodies generated?

Diabetes Metllius

due to lack of insulin action (can be as high as 90 mg/dl or 25 mM – termed ketonemia; leads to ketonuria)

Ketonemia

leads to osmotic diuresis due to ketones being passed into urine

Hyperketonemia

Up to 6 mM with prolonged fasting

diabetic ketoacidosis

25 mM due to inability to take up glucose into cells, resulting in reliance on fatty acid oxidation

Alcoholic ketoacidosis

due to metabolism of ethanol to acetate and due to low glycogen stores stemming from poor nutrition and lack of oral food intake – shifts metabolism towards fat oxidation

Ketogenic diets

Blood ketones can rise up to 3 mM potentially with ketogenic diet or self-prescribed weight loss do not achieve ketosis and may come with other costs of high fat (especially SFA) intake and high protein intake – NAFLD, atherosclerosis, kidney failure

Polyunsaturated fatty acids (PUFAs)

Act as factors to bind to the PPAR alpha receptor (nuclear receptor) to go to the target gene → inhibit maturation of SREBP1 and reduce lipogenic gene transcription

PPARa agonists (Fish oil or Fibrates)

reduce hepatic and serum TG levels