Lipid Metabolism Flashcards
Overview of fatty acid and TG synthesis
acetyl~CoA = source of all carbons acetyl~CoA comes from dietary CH2O & protein NADPH & energy (ATP) are required mostly in adipose and liver mostly during fed state (insulin) occurs in cytosol FA arrow TG (or PL)
Fatty acid synthesis is chemically the reverse of…
B-oxidation
Where does citrate shuttle ACoA out of and into for fatty acid synthesis?
Out of the mitochondria and inside of the cytosol
Describe the steps of the citrate shuttle
Citrate is going to accumulate in the mitochondria. Exits the mito and we spend an atp to get acoa back. This is going to form OAA. OAA is going to be reduced to malate with nadh and then malate will be oxidatively decarb to pyrtuvate. NADPH is also created. This cycle creates NADH but more importabliyt the electrons from NADH are put onto NADPH. Pyruvate has many fates after this (ie to OAA)
Remember COST= 1ATP/ACoA
What are the initial priming reactions of fatty acid biosynthesis?
- very large multi-enzyme complex
- growing FA chain held by acyl-carrier protein (2 different arms)
- grows by 2-C (acetyl) units, but they’re added as 3-C malonyl units
- grows from COOH end (CH3 end is added first)
What are the steps of fatty acid biosynthesis reduction and chain elongation
Stick them together, loss of CO2
Add two H, reduce ketone to alcohol
Take away water and remove double bond
Adding H from NADPH:
Switch hands and we stick the arm on a second malonyl CoA.
We now have a 6 C long fa on the second arm. Around 16-18 C long we are done with chain
To make 16 C long fa we need 7 turns of the cycle
Describe fatty acid elongation desaturation
FA synthesis stops at 16 or 18C (palmitic and stearic acid)
Elongases extend FA by 2C units
Desaturases add double bonds
We lack desaturases to insert 3 and 6 double bonds
Omega 3 and Omega 6 FA must be obtained from the diet (eaten) (plants or cold-water fish)
These are “Essential FA” – we must have them, but can’t make them
We must EAT them!
Linoleic (18:2 omega 6) and linolenic (18:3 omega 3) are EFA Arachidonate (20:4 omega 6) can be essential too
What is remodeling?
Elongation and desaturation of newly synthesized and dietary fatty acids
- allows our body to control the fatty acid composition of our membranes (PL)
- all cells have some capacity for remodeling
- probably why some dietary fat enters liver in chylomicrons and exits in VLDL particles (liver puts out what we need, not what we ate)
- Relative amounts of 3 and 6 FA can’t be adjusted
We are what we eat!!
What is the rate-limiting control point of fatty acid synthesis?
Acetyl-CoA carboxylase
What hormonal control is involved in fatty acid synthesis?
Fed state = Insulin = ON (protein phosphatase) . Insulin activates Phosphatase destroys camp to amp during fed state.
Fasting state = Glucagon = OFF (protein kinase A)
What type of allosteric control is involved in fatty acid synthesis?
Citrate (and acetyl~CoA) in cytosol activate
Palmitate (end-product) feedback inhibits
How does AMP-PK regulate FA synthesis?
AMP-PK also phosphorylates & inactivates acetyl~CoA carboxylase
AMP-PK is active when AMP is high (fasting & exercise)
decrease fatty acid synthesis & increase B-oxidation
AMP-PK is inactive when [glucose] is high - fed state - Type II diabetes
increase fatty acid synthesis & decrease B-oxidation
increase FA/TG synthesis contributes to hyperlipidemia seen in “metabolic syndrome” and Type II diabetes
Overview/review of regulation of FA synthesis in liver
- Fed State
insulin & glucose: increase activity of ACC arrow increase fatty acid synthesis - Fasting State
glucagon has opposite effects
decrease activity of ACC arrow decrease fatty acid synthesis
3) Cellular Controls
- citrate activates
- palmitoyl~CoA inhibits
4) Chronic high glucose also increase ACC activity
- hyperlipidemia/DM-II
Overview of TG/FA Catabolism
fatty acids mobilized from adipose tissue during fasting and exercise - hormone-sensitive lipase action on TG
in the blood complexed with albumin for transport in blood to tissues
activated to FA~CoA in cytosol (thiokinase)
carried into mitochondria (carnitine-shuttle)
fatty acids -oxidized back to acetyl~CoA (some ATP)
acetyl~CoA oxidized completely thru CAC to make ATP
fa are major energy sources during: - fasting = glucagon - stress/exercise = epinephrine
What does the carnitine shuttle do?
Carries FA into and out of the mitochondria
Shuttles activated FA into the mitochondria so that it can be beta oxidized.
There are defects in CPT1 and CPT2 that affect entry and exit of activate fa into and out of the matrix.
