FA synthesis and storage

lipogenesis uses what molecule as its source of reductive power? How does this compare to beta-oxidation?

Lipogenesis used NADPH as a source of reductive power

beta-oxidation required NAD+

TAGs consist of

3 FAs

glycerol back bone

What tissue/s does lipogenesis mainly occur in

liver

lesser extent in adipose tissues, kidney, brain, lungs and mammary glands

Main source of carbon in FA synthesis

carbohydrates

Where does the de novo synthesis of FA from Ac-CoA occur

in cytosol on FA synthase complex

What is the product of the FA synthase complex

Palmitate (converted to fatty acyl-coAs)

Fatty-acyl CoAs combine with ____ in the ___________ to form TAGs

Fatty acyl-CoAs combine with glycerol-3-phosphate in the liver to form TAGs

TAGs produced de novo in the liver are packaged in ___ before being secreted in the blood

VLDL

FA synthesis occurs in insulin/glucagon world

insulin world (fed state)

FA synthesis ingredients

Ac-CoA + NADPH + CO2 + ATP

There are 2 stages in FA synthesis, what us stage 1

formation of key precursor malonyl-CoA from Ac-CoA by Ac-CoA carboxylase

What does Ac-CoA carboxylase do

Converts acetyl CoA to malonyl CoA (uses biotin, ATP and CO2)

used in FA synthesis

There are 2 stages in FA synthesis, what is stage 2

elongation of the fatty acid chain (malonyl CoA) in 2 carbon increments using FA synthase

What does FA synthase do

Malonyl CoA + NADPH → FA synthase → Fatty acid palmitate`

In FA synthesis, where does the Ac-CoA come from

Citrate (TCA cycle)

In FA synthesis where does NADPH come from

HMP and PPP and malate

• Glucose → HMP shunt → NADPH

• Citrate → citrate shuttle to cytoplasm → OAA + acetyl coa

  • OAA → malate → malic enzyme → NADPH

NADPH then interacts with FA synthase to form palmitate from malonyl CoA

Isocitrate dehydrogenase inhibits/activates TCA cycle

why is this important

Isocitrate dehydrogenase inhibits TCA cycle when too much ATP and NADPH is produced

Insulin/citrate turn on this enzyme after a high carb meal → FA synthesis occurs

Isocitrate dehydrogenase is an important enzyme because it controls whether TCA cycle or FA synthesis is occuring. How does it do this?

Insulin activates this enzyme → FA synthesis occurs

Glucagon deactivates this enzyme → TCA occurs

List the possible uses for Ac-CoA described in this lecture

TCA cycle

FA synthesis precursor

Ketone body synthesis

Sterol synthesis

Ac-CoA is produced from

pyruvate

ketogenic AAs

FA oxidation

Alcohol metabolism

Glucose is converted to pyruvate via _______

enters __________

Pyruvate is converted to Ac-CoA by ___________

Glucose is converted to pyruvate via glycolysis

enters mitochondria

pyruvate is converted to Ac-Coa by pyruvate carboxylase

Once Ac-CoA is formed in the mitochondria, it cannot cross the membrane to enter the cytoplasm for FA synthesis. How does it by pass this problem

Ac-CoA + OAA condense to form Citrate

Citrate can cross the mitochondrial membrane

Ac-CoA enters the cytoplasm as OAA. Ac-CoA must revert back to Ac-CoA in order to undergo FA synthesis. How does it accomplish this?

Citrate is cleaved to OAA and Ac-CoA by citrate lyase

requires ATP

induced by insulin

Citrate lyase enzymes does what

cleaves citrate to OAA and Ac-CoA

required for FA synthesis

requires ATP

induced by insulin

Citrate synthase

catalyzes condensation of Ac-CoA and OAA

forms citrate

located in mitochondria

What stimulates transport of citrate to cytosol

when mitochondrial concentration of citrate is highE

What would cause mitochondrial citrate concentration to be high

isocitrate dehydrogenase inhibition (large amounts of ATP)

causes citrate and isocitrate accumulation

OAA from citrate lyase reaction in cytosol is further metabolized

reduced by NADH → NAD + malate

uses enzyme malate dehydrogenase

Malate dehydrogenase

in cytosol

uses NADH

reduces OAA to malate

Once generated in the cytosol, malate ……

converted to pyruvate

via malic enzyme

produces NADPH

produces CO2

pyruvate reenters mitochondria

What is the initial and controlling step for FA synthesis

Ac-CoA A carboxylase

Ac-CoA carboxylase catalyzes

conversion of Ac-CoA to malonyl-CoA

Ac-CoA carboxylase is controlled by

Activated by insulin

Activated by citrate

What is the only FA humans can synthesize de novo

palmitate

what part of the malonyl CoA is used by the FA synthase

ONLY THE AC-COA PORTION

The elongation and desaturation of long-chain FAs occurs in the

ER (FA synthase complex)

How does palmitate leave FA synthase complex once the process is completed

thioesterase

how is palmitate converted to FAs after synthesis

converted to palmityl-CoA

forms other fatty acyl-CoA molecules

fatty acyl-CoA molecules converted to TAGs

FA palmitate leaves cytoplasm and enters

SER to become TGs

TGs are assembled with what lipoprotein

apo-B100 (VLDL)

Why are alcoholics livers fatty

alcohol disrupts transport of VLDL from liver to adipose tissues

alcohol disrupts VLDL assemble → TG stay in liver → liver becomes fatty

What is the storage form of FAs

TAGs

What are TAGs made of

3 FAs to glycerol (glycerol-3-P)

TAG formation from FAs occurs primarily in

liver and adipose tissue

Liver sends TAGs to adipose tissue packaged as

VLDLs

There are 2 sources of glycerol-2-P for TAG synthesis

DHAP by glycerol-3- P dehydrogenase

• Liver and adipose tissue

Free glycerol by glycerol kinase

• liver only

During insulin world, glycerol kinase allows the liver

to recycle glycerol released during VLDL metabolism back into TAG synthesis

During glucagon world, glycerol kinase allows the liver to

trap glycerol released from adipose tissue for conversion to glucose

Cholesterol is produced in what tissue/s

all body tissues but mostly in the liver and intestine

Cholesterol and cholesterol esters are transported in the blood by

lipoproteins

All carbons from cholesterol are derived from

acetyl-CoA

The key intermediates of cholesterol biosynthesis are

HMG-CoA

mevalonic acid

isopentenyl pyrophosphate

squalene

Major regulatory enzyme for cholesterol synthesis

HMG-CoA reductase

Cholesterol is stored in tissues as

cholesterol esters

Cholesterol is synthesized from

cytosolic Ac-CoA

Major source of carbons for cholesterol synthesis

Glucose (same as FA synthesis)

In cholesterol synthesis cytosolic Ac-CoA forms __________

acetoacetyl- CoA

In cholesterol synthesis, acetoacetyl-CoA condenses with ________ to form ________

In cholesterol synthesis, acetoacetyl-CoA condenses with another Ac-CoA to form HMG-CoA

In cholesterol synthesis, HMG-CoA is reduced in the _______ to form _______ by ____________

In cholesterol synthesis, HMG-CoA is reduced in the ER to form mevalnic acid by enzyme HMG-CoA reductase

HMG-CoA reductase

located in ER

Reduces HMG-CoA to mevalonic acid

HMG-CoA reductase is inhibited by

cholesterol

In cholesterol synthesis, mevalonic acid is converted to

isopentenyl pyrophosphate

Mevalonic acid goes through a series of steps (that I dont need to know) to form

squalene

HMG-CoA is the rate limiting step in choleterol synthesis, what activates / deactivates this enzyme

insulin activates

glucagon inhibits

downstream cholesterol provides a negative feedback loop for this enzyme

What do statin drugs do

inhibit HMG-CoA reductase

inhibits cholesterol synthesis

List the lipoproteins from least to most dense

chylomicrons → VLDLs → IDLs → LDL → HDLs

Chylomicron functions

transport dietary TAGs from intestine to adipose tissues and muscles

VLDL function

transport TAGs synthesized in the liver to adipose tissues and muscles

apo-40 is associated with

chylomicrons

apoB-100 is associated with

VLDLs

Lipoprotein lipase (LPL) function/s

needed for metabolism of both chylomicrons and VLDL

hydrolyzes FAs from TAGs

activated by apoC-II

Lipoprotein lipase is induced by _____

insulin

After a heavy meal, what causes the blood serum to become turbid/ milky

chylomicrons

After TAG is removed from VLDL, the resulting particle is referred to as

IDL

LDL normal function

deliver cholesterol to tissues for biosynthesis