FA Metabolism Flashcards
TAG associated FAs serve as:
A major concentrated fuel store for the body
What is the energy yield potential of completely oxidized FAs to CO2 and water?
9 kcal/g of fat
4 kcal/g protein or carb
What does adipose lipase do?
Low level release of FAs fro adipose tissue
TAG -> DAG + FA
What does hormone-sensitive lipase do?
HSL
Has major role in regulated lipolysis and release of FAs from adipose
TAG -> DAG + FA
What does Lipoprotein Lipase do?
Releases FAs from TAG in the circulating lipoprotein particles to free fatty acids and glycerol
More complete release of FAs
Which enzyme causes the release of FAs from TAG?
(Activation of) HSL, hormone-sensitive lipase
Activation of HSL
- HSL is phosphorylated and activated by cAMP dependent protein kinases
- Phosphorylation of HSL causes:
- activation of enzymatic lipase activity
- HSL binds to perilipin (lipid droplet surface protein) - Hormone (epinephrine) mediated activation/phosphorylation of HSL to generate FAs
- epinephrine binds GPCR indirectly activating adenylyl cyclase via Ga(s)
- adenylyl cyclase generates cAMP
- cAMP activates cAMP-dependent protein kinases
- cAMP-dependent protein kinases phosphorylate HSL
What is perilipin?
Lipid droplet surface protein.
HSL binds to this once phosphorylated to release FAs
HSL is activated by:
Phosphorylation by cAMP dependent protein kinases.
What can deactivate FA synthesis?
Epinephrine
How does epinephrine deactivate FA synthesis?
Epinephrine binds to GPCR indirectly activating adenylyl cyclase via Ga(s)
Adenylyl cyclase generates cAMP
cAMP activates cAMP-dependent protein kinases
cAMP dependent protein kinases phosphorylated and deactivate ACC
Carboxylation of acetyl CoA -> melonyl CoA by acetyl CoA carboxylase is inhibited
Carbon-to-carbon condensation reactions inhibited
FA synthesis stops
How else can FA synthesis be turned off?
Insulin promotes dephosphorylation of HSL by activated phosphatases.
This shuts off HSL catalyze do hydrolytic release of FAs from TAG
What can turn off FA synthesis?
Epinephrine and insulin
What do adipocytes lack? What does this mean?
Glycerol kinase
Therefore they cannot metabolize glycerol released in TAG degradation
What happens to the glycerol from TAG degradation of adipose tissue?
It is released to the blood and taken up by the liver
Then phosphorylated in the liver to be used in TAG synthesis
OR
Reversible converted to DHAP by glycerol phosphate dehydrogenase
DHAP can participate in glycolysis or GNG
What does glycerol phosphate dehydrogenase do?
Converts glycerol back to DHAP (for glycolysis or GNG)
DHAP can be fed into..
Glycolysis or GNG
Free FAs leave adipocytes to the..
Blood, where they bind serum albumin
From the blood, FAs are…
Taken up by cells and are activated to CoA by fatty acyl CoA synthetase (thiokinase)
Fatty acyl CoA is..
Oxidized for energy production/release
What two things don’t use FAs for energy, and why?
Brain because idk
Erythrocytes because no mitochondria
What is the major pathway for obtaining energy from FAs?
Beta-oxidation
Where does beta oxidation occur?
In the mitochondria
For B-oxidation, FAs must be in what form?
Fatty Acyl CoA
What are the products of B-oxidation?
Acetyl CoA, NADH, FADH2
How are LCFAs transported into the mitochondria?
From the blood.
What does LCFA CoA synthase do? Where is it found?
Generates LCFA CoA
On the cytosol(ic side of the mitochondrial outer membrane)
What can’t LCFA CoA cross the inner membrane of the mitochondria?
The presence of CoA
What is the Carnitine Shuttle Process?
Import of LCFAs into the mitochondria
Requires specialized transport
Steps of the Carnitine Shuttle Process
- Acyl groups are transferred from CoA to Carnitine
- Acyl Carnitine is transported into the mitochondrial matrix in exchange for free Carnitine
- CAT-II on the matrix side of the inner mitochondrial membrane catalyzes Acyl group transfer from Carnitine to CoA
What inhibits the Carnitine Shuttle?
Malonyl CoA, inhibits CAT-1, preventing LCFA transfer from CoA to Carnitine
Prevents mitochondrial import and B-oxidation of newly synthesized LCFAs
B-oxidation of LCFAs to generate energy while in well-fed state
What is the source of Carnitine?
From diet of synthesized.
Diet: meat products
Synthesized: an enzymatic pathway in liver and kidney
What stores Carntine but doesn’t synthesize it?
Skeletal muscle.
97% of Carnitine
Relies on uptake of synthesized and dietary sources from the blood
Carnitine deficiency reduces:
The ability of tissues to use LCFA as a metabolic fuel
Secondary Carnitine deficiencies are caused by:
Decreased synthesis due to liver disease
Dietary malnutrition or a strict vegetarian diet
Hemodialysis, which removes Carnitine
Conditions when Carnitine requirements increase (pregnancy, severe infections, burns, trauma)
Primary Carnitine Deficiency are caused by:
Congenital deficiencies in:
Renal tubular reabsorb toon of Carnitine
Carnitine uptake by cells
CAT1 or CAT2 function (genetic defects)
Treatment of Carnitine deficiencies
Avoid prolonged fasts
High carbs/low LCFA diet
Supplement with medium chain FAs and Carnitine
How do short and medium chain FAs enter the mitochondria? Then what happens?
Without Carnitine or CAT1/2 systems
They’re activated to CoA derivatives by thiokinase
Human milk is high in:
Short and medium chain FA
What is B-oxidation?
4 reaction sequence involving the beta carbon, each successive round shortens the FA chain length by 2 carbons
Steps of b-oxidation
- Acyl CoA dehydrogenase (produces FADH2)
- Enoyl CoA hydrolase (hydration step)
- 3-hydroxyacyl CoA dehydrogenase (produces NADH)
- thiolytic cleavage (releases acetyl CoA)
Energy yield from FA Oxidation (beta oxidation)
High!
1 palmitoyl CoA to CO2 and H2O yields a net 129 ATP
B-Oxidation of FAs with an odd number of carbons
Produces a 3-carbon product, Propionyl CoA
Metabolism of Propionyl CoA pathway
- Synthesis of D-methylmalonyl CoA
- Propionyl CoA is carboxylated - Formation of L-methylmalonyl CoA -> methylmalonyl CoA, via isomer conversion
- Synthesis of Succinyl CoA, carbons are rearranged to form Succinyl CoA to enter the TCA cycle
Glycogenic precursor generated from FA oxidation
Succinyl CoA, via B-oxidation of FA with odd number of carbons
Since B-oxidation of FA produces Propionyl CoA
Vitamin B12 deficiency causes:
Excretion of both propionate and methylmalonate in the urine
Result in metabolic acidosis (possibly retardation)
Unsaturated FAs release _____ energy than saturated FAs
Less
Why do unsaturated FAs release less energy than saturated FAs?
They require additional enzymes
Where are VLCFAs initially oxidized?
In the peroxisome.
Does peroxisomal B-oxidation generate ATP?
Nope.
Genetic defects that result in failure to target matrix proteins to the peroxisome ***
Zellweger syndrome (peroxisome biogenesis disorder)
Genetic defects that cause the failure to transport VLCFA across the peroxisome membrane ***
X-linked adrenoleukodystrophy
Zellweger syndrome and X-linked adrenoleukodystrophy cause:
The accumulation of VLCFA in blood in tissues
Why can’t phytanic acid act as a substrate for acetyl CoA dehydrogenase (in B-oxidation)?
Because there is a methyl group at it’s B-Carbon.
What is phytanic acid?
FA chain, branched, 20-carbon long
Cannot undergo B-ox due to methyl at B-carbon
What does paytanoyl CoA alpha-hydroxylase (PhyH) do?
Hydroxylates the alpha carbon and carbon 1 is released as CO2
19-C Pristanic Acid is then activated to CoA and undergoes B-oxidation
What is Refsum disease?
Rare, autosomal, recessive disease
Caused by peroxisome last PhyH deficiency
Accumulation of Phytanic acid in blood and tissues
Neurological symptoms.
Treatment: dietary restrictions to halt disease progression……
There are 4 mitochondrial fatty acyl CoA dehydrogenases why?
For chain specific length:
Short, medium, long, and very long
MCAD deficiency
Decreased oxidation of 6-10 carbon FAs (medium chain)
Accumulation can be measured in the urine
Symptoms: severe hypoglycemia, since tissues rely on glucose
Treatment: avoid fasting
Autosomal, recessive
What is one of the most common inborn errors of metabolism?
And most common inborn error or FA oxidation
MCAD deficiency
What disease has been identified as a possible cause for SIDS or Reye syndrome?
MCAD deficiency
SIDS=sudden infant death syndrome
What are ketone bodies used for?
An alternate fuel for cells (instead of TAG/FAs)
Where are ketones produced?
In liver mitochondria,
From b-oxidation derived Acetyl CoA
Where 3 metabolic products come from ketone bodies?
Acetoacetate
3-hydroxybutyrate
Acetone
What 2 ketone bodies are transported in the blood to peripheral cells/tissues?
Acetoacetate and 3-hydroxybutyrate
Which ketone body is a dead-end byproduct?
Acetone
Peripheral cells convert ketone bodies back into…
Acetyl CoA, a substrate for the TCA cycle
Why are ketone bodies converted in peripheral cells?
Because they’re an important energy source for them
Are ketone bodies soluble in aqueous solution?
Yes, they can be transported throughout blood without lipoprotein or albumin transport
When are ketone bodies produced?
When Acetyl CoA levels supersede oxidation capacity
What tissues can utilize ketone bodies?
Extra-hepatic tissues such as HEART and SKELETAL MUSCLE, and RENAL CORTEX
BRAIN can utilize ketone bodies for energy source if levels are sufficient
What are the extra-hepatic tissues that use ketone bodies?
Heart, skeletal muscle, and renal cortex
When can the brain utilize ketone bodies?
When levels are sufficient
Ketone bodies decrease the demand on:
Blood glucose
When are ketone bodies particularly important?
During prolonged fasting!
What are the 2 FA oxidation disorders
Hypoketosis and hypoglycemia
What is the FA oxidation disorder disorder associated with decreased Acetyl CoA availability?
Hypoketosis…less Acetyl CoA, less ketone bodies.
What is the FA oxidation disorder associated with increased reliance on glucose for energy?
Hypoglycemia. Increased reliance on glucose = less glucose
What is Ketogenesis?
Ketone body synthesis
What happens to FAs during fasting?
They accumulate in the liver.
Increased hepatic Acetyl CoA inhibits and activates..
Inhibits pyruvate dehydrogenase
Activates pyruvate carboxylase (then OAA is produced)
Steps of Ketogenesis
- Formation of acetoacyl CoA
- HMG CoA synthase combines a 3rd molecule of Acetyl CoA with acetoacyl CoA to generate HMG CoA
* ***rate limiting - HMG CoA is cleaved to produce acetoacetate (and Acetyl CoA as byproduct)
4a. Acetoacetate can be reduced to 3-hydroxybutyrate with NADH as the hydrogen donor
4b. Acetoacetate can spontaneously decarboxylate to form acetone in the blood
What is the rate-limiting step of Ketogenesis?
HMG CoA Synthase combines a 3rd molecule of Acetyl CoA with acetoacyl CoA to generate HMG CoA
HMG CoA Synthase is present only in the liver (to significant amounts)
What is Ketolysys?
Use of ketone bodies in peripheral tissues.
Steps of Ketolysys
- 3-hydroxybutyrate is oxidized to acetoacetate by 3-hydroxybutyrate dehydrogenase, producing NADH in peripheral tissues
- Acetoacetate is then provided with a CoA molecule taken from Succinyl CoA by a thiophorase
- Acetoacyl CoA is converted to 2 Acetyl CoA’s
What cells can undergo Ketolysys?
Extrahepatic cells with mitochondria.
Why can’t the liver undergo Ketolysys?
It lacks thiophorase.
What does thiophorase do?
In Ketolysys, converts acetoacetate into Acetoacyl CoA (which then is converted into Acetyl CoA)
What is ketonemia?
High levels of ketone bodies in the blood
What is Ketonuria?
High levels of ketone bodies in the urine
When can ketonemia and Ketonuria occur?
In type 1 diabetes mellitus
Remember that: Glucose level is _______ in diabetes.
High
What is noticeable from Diabetic Ketoacidosis?
Fruity smelling breath from acetone
