Block 3 Fatty Acid Oxidation Flashcards
What are fatty acids? Where are they found?
Carboxyl group + long hydrocarbon chain 4-24C; part of lipid molecule or complexed to carrier protein like albumin
What length are SC, MC, LC, VLC FAs? What happens with increasing chain length? What length are dietary and stored FAs?
SC: 2-4C, MC: 6-12C, LC: 14-20, VLC: <22
Decreased solubility, fluidity, increased melting point
16-18C (mix of sat, MU, PU)
What is 18:0 fatty acid?
Stearic acid (octadecanoic acid)
What is 18:1 d9?
Oleic acid (octadecenoic acid)
What is 18:2 d9,12?
Linoleic acid (octadecadienoic acid)
What is 18:3 d9,12,15?
Alpha-linolenic acid (octadecatrienoic acid)
What are the sources of FAs and how are is their energy used in peripheral tissues?
Fed state: dietary TGs to CMs stored
Fasted: TAG in adipose -> FA (gluc/epi) on albumin to be oxidized
Postprandial: TAG synth in liver -> carb exported on VLDL stored/oxidized
What is b-oxidation?
Major in mito (PUFA and sat, LC and MCFA, provides NADH and FADH2); peroxisomal (VLCFA)
What are alpha and omega oxidation?
A: peroxisomal pathway for branched chain FAs
O: microsomal pathway for detoxifying lipid molecules
What are the steps of FA ox?
Transport into cell, activation by FaCoA (cytosol), transport into mito (carnitine shuttle), B-ox to AcCoA
Where does AcCoA from beta oxidation go?
Fed state: oxidation in TCA
Fasted: in liver makes ketone bodies, then in peripheral tissues ketone -> AcCoA oxidized
What is a thiokinase?
Acyl-CoA synthase, specific to FA length; to esterify FA to CoA, ATP-dependent (2 ATP), on ER and OMM
What is a CPT?
Carnitine palmitoyl transferase, catalyzes transfer of FA between thiol of CoA and hydroxyl on carnitine to move FA across mito membrane
What is carnitine?
Can be synth in body, precursor trimethyllysine, essential in infants, in red meat and dairy, not soy
What are the 3 steps of carnitine-mediated transfer of FA into mito matrix?
1) CPT 1 transfers FA from CoA to OH on carnitine
2) Antiporter in IMM exchanges carnitine for acyl-carnitine
3) CPT2 in matrix transfers FA from carnitine to CoA
What is the main regulated step of FA transport? What does it?
FA entry into mito; malonyl-CoA (precursor for FA synth, from AcCoA by AcCoA carboxylase) inhibits CPT1
Where are the acyl-CoA DHs located?
All soluble in mito matrix but VLC bound to IMM
What are the enzymes responsible for steps 2-4 of B-ox?
Enoyl-CoA hydrolase, b-hydroxyacyl-CoA DH, acyl-CoA acetyltransferase (thiolase); all soluble in matrix but membrane-bound in trifxl protein for long chain FAs
What is the reaction for one round of B-ox?
Fatty acyl-CoA + FAD + NAD+ + HS-CoA -> fatty acyl-CoA (-2C) + FADH2 + NADH + H+ + AcCoA
What are the products of B-ox if the FA has an even or odd number of carbons?
Even: butyryl-CoA -> 2 AcCoA
Odd: AcCoA + proprionyl-CoA (liver -> glucose synth)
How is B-ox regulated by insulin and energy change?
Insulin increases FA synth in liver, increasing malonyl-CoA (1st step), inhibiting CPT1
Energy: high ATP = low ETC, increasing [NADH], inhibiting B-ox
What is the main source of odd-chain FAs? Why?
Milk fat because cow GI bacteria makes C3 propionate
How is propionyl-CoA metabolized?
Propionyl-CoA carboxylase + biotin -> 4C D-methylmalonyl-CoA + MM-CoA epimerase -> L-MM-CoA + MM-CoA mutase + B12 -> succinyl-CoA (TCA -> OAA -> glucose)
How are VLCFA oxidized?
Within peroxisomes and mito; perox do not use carnitine, but export acyl-carnitines (product of COT/CAT)
What are the products of perox B-ox?
FADH2, NADH, no ATP directly
What are Zellweger syndrome and X-linked adrenoleuko-dystrophy?
Z: lack of functional peroxisomes
XALD: defect in perox ox of VLCFA
What is alpha-oxidation?
Branched chain FA, in perox; chlorophyl -> phytanic acid (methyl on beta-C = no B-ox); alpha removes a C = substrate for B-ox
What is Refsum disease?
Neurological damage from genetic deficit in alpha-oxidation and abnormal metabolites
What is omega oxidation?
Ox of methyl C to dicarboxylic acid in microsomes, uses CytP450; to convert xenobiotics and FA metabolites (like PGs) to soluble compounds
What does MCADD lead to?
Accumulated C8/10 FAs -> dicarboxylic acids by w-oxidation
What are ketone bodies?
In fast, ox of FA incomplete b/c depletion OAA (gluconeo) so AcCoA can’t enter TCA, 4C acetoacetate and b-hydroxybutyrate released into blood
When and where are ketones utilized?
Fasting: TCA active in mm, heart, brain; primary use in mm, brain if prolonged fast; can cross placenta to fetus and fetal brain
How are ketones utilized in fast?
B-HB + DH -> acetoacetate + sucCoA-acetoacetate transferase -> acetoacetyl-CoA (OR: instead of sucCoA, ATP + CoASH -> aa-CoA + AMP + PPi) + thiolase -> 2 AcCoA
What are the products of acetoacetate following DH or decarboxylation?
B-HB DH -> B-HB (reversible, major ketone in blood)
Spontaneous DC -> acetone (excreted)
Why are children more prone to ketosis than adults? What are common causes?
More energy use/kg body mass, higher brain/liver ratio, liver glycogen stores depleted more rapidly; mild infections that may cause anorexia and vomiting
What is a ketogenic diet? When is it recommended? What TGs are best for it?
High fat (3:1 lipid to carb cals) to reduce freq epileptic seizures, in kids with PD deficiency; MCFA more ketogenic than normal dietary C16-18 bc oxidized rather than stored in TAG or PM
What might be affected by mutation to cause a B-ox disease?
PM FA transporter CD36, CPT1/2, AcCoA DH, hydroxyacyl-CoA DH (M/SCFA), medium chain b-ketothiolase, trifxl protein complex, ETF (ET flavoprotein)
What are common symptoms of B-ox disease?
Hypoketotic hypoglycemia, fatty degeneration of liver, heart/sk mm defect, maternal preg complications, SIDS
What is MCADD?
FA partially ox, C8/10 found in blood and urine, C8/10 dicarboxylic acids and acyl-carnitines; tx with diet & exogenous carnitine to replace losses
What is systemic carnitine deficiency?
Cardiomyopathy, sk mm weakness, hepatomegaly, elevated liver enzymes; hypoketotic hypoglycemia; imparied ox LCFA (normal MCFA use); defect in OCTN-2 so kidney can’t reabsorb carnitine and mm can’t acc against gradient; tx carnitine and high carb/low fat diet
