Fatty Acid Metabolism Flashcards
energy yield of completely oxidized FA to CO2 and water is…
9kcal/g
energy yield of protein and carb
4kcal/g
what is the energy yield for alcohol
7kcal/g
Acetyl CoA
- NOT being used for making glucose
- used to make ketone bodies
adipose lipase
constitutive, low level release of FA from adipose, TAG–DAG + FA
Hormone-sensitive lipase (HSL)
has a major role in regulated TAG lipolysis and release of FA from adipose, TAG—DAG+FA
- sensitive to epinephrine
- trauma/stress, drop in glucose levels
lipoprotein lipase
releases FA from TAG in the circulating lipoproteins particles to free FA and glycerol (potentially a more complete release of FAs)
What is HSL phosphorylated and activated by?
cAMP dependent protein kinases
phosphorylation of HSL causes:
- activates its enzymatic lipase activity
- HSL binding to perilipin
- fasting=phosphorylation
perilipin
- lipid droplet surface protein
- phosphorylated HSL binds to it
hormone (epinephrine) mediated activation/phosphorylation of HSL to generate FA
- 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 phosphorylate HSL
hormone mediated deactivation of FA synthesis via phosphorylation of ACC
- 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 phosphorylate and deactivate acetyl CoA carboxylase (ACC)
- carboxylation of acetyl CoA—melonyl CoA by acetyl coA carboxylase is inhibited
- carbon to carbon condensation reactions inhibited
- FA synthesis stops
insulin and HSL
- insulin promotes dephospho rylation of HSL by activating phosphatase
- This shuts off HSL catalyzed hydrolytic release of FA from TAG
- won’t produce ACC
what do adipocytes lack?
glyverol kinase
cannot metabolize glycerol released in TAG degradation if all FAs are released from a TAG molecule
glycerol is:
-released into the blood and taken up by the liver
-phosphorylated in the liver to be used in TAG synthesis
OR
-reversibly converted to DHAP by glycerol phosphate dehydrogenase
DHAP
can participate in glycolysis or gluconeogensis
FA are taken up by cells and…
activated to CoA by fatty acyl CoA synthetase (thikinase)
what tissues do not use FA for energy?
brain and erythrocytes
- erythrocytes have no mitochondria
- not clear why brain doesn’t use them
what happens to 50% of free fatty acids released from adipose TA?
they are reesterified to glycerol 3-P. this process functions to decrease the plasma free FA level associated with insulin resistance in type 2 DM and obesity
what is the major pathway for obtaining energy from FA?
B-oxidation
B-oxidation occurs where?
mitpchondria
what form must the FA be in for B-oxidation?
fatty acyl CoA
what does B-oxidation involve?
successive removal of 2-carbon fragments removed from the carboxyl end
products of B-oxidation
acetly CoA, NADH, FADH2
transport of LCFA into the mitochondria
- LCFAs enter a cell from the blood
- LCFA CoA synthase (thiokinase) located on the cytosolic side of the mitochondria outer membrane and generates LCFA CoA in the cytosol
- LCFA CoA CANNOT directly cross the inner membrane of the mitochondria due to the presence of the CoA
LCFA CoA synthase
- thiokinase
- located on the cytosolic side of the mitochondrial outer membrane and generates LCFA CoA in the cytosol
LCFA CoA in regards to the inner membrane of the mitochdondria
-cannot cross due to the CoA
carnitine shuttle process
- imports LCFAs into the mitochondria
- long chain acyl groups require specialized transport into the mitochondria
- acyl groups are transferred from CoA to carnation by carnation acyl transferase-1 (CAT-1) on outer mitochondrial membrane enzyme
- acyl carnitine is transported into the mitochondrial matrix in exchange for free carnation bt carnation-acyl carnation translocase
- CAT-II on the matrix side of the inner mitochondrial membrane catalyzes acyl groups transfer from carnation to CoA
CAT-1
- outer mitochondrial membrane enzyme
- transfers acyl groups from CoA to carnitine
carnitine -acyl carnitine translocase
transports acyl carnitine 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 carnation to CoA
inhibitor of the carnation shuttle
-CAT-I inhibited by malonyl CoA
Cat-I inhibition
- inhibited by malonyl CoA
- prevents LCFA transfer from CoA to carnitine
What does the inhibition of CAT-I by malonyl CoA prevent?
- mitochondrial import and B-oxidation of newly synthesized LCFAs
- B-oxidation of LCFAs to generate energy while in the well fed state
source of carnitine
obtained from diet or synthesized
- primarily in meat products
- synthesized by an enzymatic pathway in the liver and kidney using AA lysine and methionine
Where does 97% of carnitine reside in the body?
skeletal muscle
-must rely on uptake of synthesized and dietary sources from the blood
carnitine defficieny
reduces the ability of tissues to use LCFA as a metabolic fuel
secondary carnitine deficiencies
caused by
- decreased synthesis due to liver disease
- dietary malnutrition or a strict vegetarian diet
- hemodialysis, which removes carnation
- conditions when carnation requirements increase (pregnancy, severe infections, burns, trauma)
primary carnitine deficiencies
caused by congenital deficiencies in
- renal tubular reabsorption of carnation
- CAT-I or CAT-II function
- treatment
- avoid prolonged fasts, adopt a diet high in carbs and low in LCFA, supplement with MCFA and carnitine
CAT-I deficiency in primary carnitine deficiencies
decrease liver use of LCFA during a fast: severe hypoglycemia, coma, death
CAT-II genetic defect in primary carnation deficiencies
heart and skeletal muscle exhibits symptoms that range from cardiomyopathy to muscle weakness with myoglobinemia following prolonged exercise
entry of short and medium chain FA into the mitochondira
- FA ,12 carbons cross the inner mitochondrial membrane without carnitine or CAT-I/II systems
- activated to CoA derivatives by thiokinases
human milk
high in short/medium chain FA and not dependent on carnation or CAT-I to cross mitochondrial membrane.
oxidation of MCFA
not regulated by malonyl CoA inhibitory affects on CAT-I
B-oxidation of a fatty acyl CoA
- 4 steps involving B-carbon
- each round shortens the chain length by 2 carbons
- acyl CoA dehydrogenases: ox reaction producing FADH2
- enoyl CoA hydrolase: hydration step
- 3-hydroxyacyl CoA dehydrogenase: a second oxidation reaction produces NADH
- a thiolytic cleavage: releasing actely CoA
How are the 4 steps repeated in B-oxidation of fatty acyl CoA?
- repeated for saturated FA
- repeated: (n-2)/2 for FA with even number of C
- repeated (n-3)/2 for FA with odd number of C
what is acetyl CoA a positive allosteric effector for?
pyruvate carboxylase linking FA oxidation and gluconeogenesis
Energy yield from FA oxidation
- energy yield from B-oxidation is high
- degrading 1 palimitoyl CoA (16C) to CO2 and H20 results in a net 129 ATP
can CoA go to GNG?
no
greatest flux through pathway in FA synthesis
after carbohydrate rich meal
greatest flux through pathway in B-oxidation of FAs
in starvation
hormonal state favoring pathway in FA synthesis
high insulin/glucagon ratio
hormonal state favoring pathway in B-oxidation of FAs
low insulin/glucagon ratio
major tissue site for FA synthesis
primarily liver
major tissue site for B-oxidation
muscle, liver
subcellular location of FA synthesis
primarily cytosol
subcellular location of B-oxidation
primarily mitochondria
carriers of acyl/acetyl groups between mitochondria and cytosol in FA synthesis
citrate (mitochondria to cytosol)
carriers of acyl/acetyl groups between mitochondria and cytosol in B-oxidation
carnitine (cytosol to mitochondria)
Phosphopantetheine-containing active carriers in FA synthesis
acyl carrier protein domain, CoA
Phosphopantetheine-containing active carriers in B-oxidation
CoA
oxidation/reduction coenzymes in FA synthesis
NADPH (reduction)
oxidation/reduction coenzymes in B-oxidation
NAD+, FAD (oxidation)
two carbon donor/product of FA synthesis
malonyl CoA: donor of one acetyl group
oxidation/reduction coenzymes in B-oxidation
acetyl CoA; product of B-ox
activator of FA synthesis
citrate
inhibitor of FA synthesis
-long chain fatty acyl CoA (inhibits acetyl CoA carboxylase)
inhibitor in B-oxidation
malonyl CoA (inhibits carnitine palmitoyltransferase-I)
product of FA synthesis
palmitate
Product of B-oxidation
Acetyl CoA
repetetive 4 step process in FA synthesis
- condensation, reduction
- dehydration, reduction
repetetive 4 step process of B-oxidation
- dehydrogenation, hydration
- dehydrogenation, thiolysis
B-oxidation o FA with an odd number of C
similar to that of even number of carbons with the exception that the final thiolytic cleavage produces a 3-C product: propionyl CoA
What is the product of B-oxidation of a FA with an odd number of C?
propionyl CoA
How is Propionyl CoA metabolized?
- synthesis of D-methylmalonyl CoA: propionyl CoA is carboxylated by propionyl CoA carboxylase
- formation of L-methylmalonyl CoA: D to L-methylmalonyl CoA isomer conversion by methylmalonyl CoA racemase
- synthesis of saucily CoA: the carbon of L-methylmalonyl CoA are rearranged to form saucily CoA by methylmalonyl CoA mutters: saucily CoA enters the TCA cycle
What is the end product of B oxidation of a FA with an odd number of carbons
succinyl CoA
Vitamin B12 deficiency in FA
- causes excretion of both propionate and methylmalonate in the urine
- heritable methylmalonic acidemia OR aciduria is possible
- both result in metabolic acidosis, potential for developmental retardation
B oxidation in the peroxisome
- VLCFA are initially oxidized in the peroxisome
- peroxisomal B-oxidation does not generate ATP
Zellwegger syndrome
a peroxisome biogensis disorder
- genetic defects that result in failure to target matrix proteins
- Cause the accumulation of VLCFA in the blood and tissues
X-linked adrenoleukodystrophy
- genetic defects causing the failure to transport VLCFA across the peroxisomal membrane.
- disconnect in sensing environment
- Cause the accumulation of VLCFA in the blood and tissues
a-oxidation of FA
- branched-chain, 20-C FA phytanic acid cannot function as a substrate for acetyl CoA dehydrogenase due to the methyl group at its B-carbon
- paytanoyl CoA a-hydroxylase (PhyH) hydroxylates the a-carbon and carbon 1 is released as CO2
- 19 carbon pristanic acid is activated to CoA and undergoes B-oxidation
Refsum disease
- rare, autosomal, recessive: caused by peroxisomal PhyH deficiency
- phytanic acid accumulates in the blood and tissues
- symptoms are primarily neurologic
- treatment requires dietary restrictions to halt disease progression
medium chain fat acyl CoA dehydrogenase deficiency
- decreased oxidation of 6- to 10- carbon FA
- medium chain length FA accumulate; can be measured in the urine
- avoid fasting
- one of the most common inborn errors of metabolism
- the most common inborn error of FA oxidation
what is the most common inborn error of FA metabolism/oxidation?
MCAD deficiency
Ketone bodies
- soluble in aqueous solution (no lipoprotein or albumin transport required)
- produced in liver when acetyl CoA levels supersede oxidation capacity
- use is proportional to concentration in the blood by:
- extra-hepatic tissues such as heart, skeletal muscle, and renal cortex
- brain can utilize ketone bodies for energy source if levels are sufficient
Why are ketone bodies important during fasting?
ketone bodies decrease the demand on blood glucose
hypoketosis
due to decreased acetyl CoA availability
hypoglycemia
due to increased reliance on glucose for energy
ketogensis
- during fast
- FA accumulates in liver
- increased hepatic acetyl CoA
- OAA used fir GNG (not used in TCA cycle)–acetly CoA is channeled into ketone body synthesis
- FA oxidation decreases the NAD+:NADH ratio and the increased NADH shifts the OAA to malate
- formation of malate shifts acetyl CoA away from GNG, toward ketogenesis
what does increase hepatic CoA do?
- inhibitis pyruvate dehydrogenase
- activates pyruvate carboxylase…OAA is produced
synthesis of HMG CoA: formation of acetoacetyl CoA
-reversal of the thiokinase reaction of FA oxidation step 4
synthesis of HMG CoA: HMG CoA synthase
- combines a third molecule of acetyl CoA with acetoacyl CoA to generate HMG CoA
- HMG CoA synthase is the rate limiting step in ketone body synthesis and it present only in the liver to significant amounts
synthesis of HMG CoA: HMG cleavage
HMG CoA cleaved to produce acetoacetate and acetyl CoA
synthesis of HMG CoA: reduction of acetoacetate
acetoacetate can be reduced to 3-hydroxybutyrate with NADH as the hydrogen donor
synthesis of HMG CoA: formation of acetone
- acetoacetate can spontaneously decarboxylate to form acetone in the blood
- acetone is a volatile, biologically non metabolizes compound that is released in the breath
ketone bodies in peripheral tissues
3-hydroxybutyrate is oxidized to acetoacetate by 3-hydroxy butyrate dehydrogenase, producing NADH in peripheral tissues
What happens in peripheral tissues when 3-hydroxybutyrate is oxidized to avetoacetate?
- acetoacetate is then provided with a CoA molecule taken from saucily CoA by saucily CoA: acetoacetate CoA transferase (thiophorase)
- acetoacetyl CoA is converted to (2) acetyl CoA and goes to TCA
Can liver use ketone bodies?>
no, it lacks thiophorase
excess of ketone bodies in DM
- ketonemia (ketone rise in blood)
- KEtonuria (ketone rise in urine)
diabetic ketoacidosis
- fruity breath from acetone
- increased ketone bodies and glucose
- decreased blood volume increases H+ concentration causing severe acidosis
- can be caused by fasting
