Biochem: fatty acid metabolism

explain saturated vs unsaturated fats/fatty acids

unsaturated: has double bonds

saturated: no double bonds

fat is stored as ____ which is ____

triacylglycerols/triglycerides: glycerol + 3 fatty acids

note that for fatty acid breakdown, the fatty acids first have to be taken off of the TG

what are the two essential fatty acids? why are they called essential?

linoleate and linolenate; they are essential because we must consume them, we cannot synthesize them

explain the difference in the presence of glucose vs fatty acids in the blood

fatty acids are removed form the blood by tissue quickly, so there is low amounts of FAs in the blood and more glucose in the blood

what organs prefer glucose and which organs prefer fatty acids for fuel?

fatty acids: liver and muscles

glucose: RBCs and brain

____ provides most of the calories for the body under most conditions including rest, prolonged exercise, and starvation

fatty acids

what is the enzyme lipase responsible for with the breakdown of fatty acids?

lipase does the first “pre-step” where the fatty acids are taken out of storage (removed from the triglycerides)

what is the main site of regulation of fatty acid breakown?

lipolysis by lipase (catalyzes the first “pre-step” of FA metabolism)

How does insulin affect fatty acid metabolism?

can act on hormone sensitive lipase (1st pre-step where the FA are removed from the TGs in storage)

insulin: released when we are fed; inactivates the lipase to decrease fatty acids being broken down

How does glucagon affect fatty acid metabolism?

hormone sensitive lipase (the lipase that does the 1st pre step) is activated by glucagon to start the breakdown of fatty acids

glucagon is released in the fasting state

fasting and fed state: insulin and glucagon, which one goes with which?

fed: insulin

fasting: glucagon

How are free fatty acids transported in the blood?

they are bound to serum albumin

where is the site of fatty acid metabolism?

mitochondria

pre-steps of fatty acid breakdown: after lipase removed the fatty acids from the triglycerides, what is the next step?

the FAs have to be activated by adding coenzyme A by fatty acyl CoA synthetase

what is the rate limiting step of the oxidation of long chain fatty acids?

transport into the mitochondrial matrix by CTP-I

what enzyme catalyzes the rate limiting step of the oxidation of long chain fatty acids?

CPT-I (transports the FAs into the mitochondria to start the oxidation/metabolism)

transport across the inner mitochondrial membrane by CPT requires ______ to be attached to the fatty acid

carnitine (hence the CPT being a carnitine translocase)

How does malonyl CoA affect FA oxidation and how?

CPT-I inhibited by malonyl CoA to stop the oxidation of FA

(malonyl CoA is an intermediate of fatty acid synthesis, so if it is around then we are making FAs and do not need to be also breaking them down)

when fatty acid synthesis is not occurring then malonyl CoA is ____

it is decreased → then CPT-I is not being inhibited and we can break down FAs

long chain fatty acids must use the ___ system

short chain and medium chain fatty acids enter the mitochondria via _____

carnitine transport system

simple diffusion

very long chain fatty acids cannot enter the mitochondria, instead what must happen?

they diffuse into peroxisomes where they are oxidized to shorter chains, then they can enter the mitochondria and do regular oxidation/breakdown

Even chain fatty acids go through ___ oxidation

beta oxidation

beta-oxidation of even chain fatty acids produces what?

per cycle: you change 2 carbons for 1 acetyl CoA, you also get 1 NADH and 1 FADH2

What enzyme catalyzes the first actual step of beta oxidation of fatty acids (once they are already in the mitochondria)?

acyl CoA dehydrogenase

What do we see with medium-chain fatty acyl CoA dehydrogenase deficiency?

severe hypoglycemia and hypoketonemia (basically your body cannot break down the medium chain fatty acids for energy so you use up all the glucose and ketone bodies in your blood)

tx: avoid fasting

What clinical correlate?

we see severe hypoglycemia and hypoketonemia; treat by avoiding fasting

medium-chain fatty acyl CoA dehydrogenase deficiency

explain the ATP yield for glucose vs fatty acid metabolism

fatty acid metabolism is a better bang for your buck

33% greater ATP yield than form glucose

How do AMP and PKA affect fatty acid metabolism?

they promote FA breakdown;

PKA and AMP inhibit Malonyl CoA (no synthesis of FAs) so then CPT-I is not inhibited and can transport the FAs into the mitochondria for breakdown

explain the oxidation of unsaturated fatty acids

they have a cis bond, so isomerase has to convert that to a trans bond before oxidation can proceed

note: these are the “healthier fats” because our body has to work harder to break them down

explain the oxidation of fatty acids that have an odd number of carbons

each cycle of oxidation removes two carbons, so at the end you are left with 3 carbons instead of 2; those 3 carbons are released as propionyl CoA (rather then acyl CoA)

the propionyl CoA then gets converted to succinyl CoA: requires biotin and vit B-12

what required vit B-12 and biotin and why?

oxidation of odd numbered fatty acids (propionyl CoA is made rather than Acyl CoA)

What clinical correlate?

pts born blind, deaf, unable to eat, and die by 6 months of age

Zellweger syndrome

What is this?

absence of peroxisomes which leads to the accumulation of very long chain fatty acids (because they cannot be broken down to enter the mitochondria without peroxisomes)

Zellweger syndrome

What is phytanic acid?

branched fatty acids

branched fatty acids go through ___ oxidation

alpha

A defect in alpha-oxidation (needed to oxidize branched fatty acids) is known as

Refsum’s disease

What clinical correlate?

ataxia, neuropathy, and retinitis pigmentosa

Refsum’s disease (defect in alpha oxidation so no oxidation of branched fatty acids)

What helps get rid of unwanted acids and foreign compounds with fatty-acid like structure?

omega oxidation

what is an alternative fuel during fasting and stavation?

ketone bodies

during long term starvation, the ___ oxidizes fat to produce ___ and releases them into the blood for the other tissues to use as energy

liver; ketone bodies

What are these?

acetoacetate, beta-hydroxybutyrate, and acetone

ketone bodies

ketone bodies are ____ and do not need ____

soluble in aqueous solutions so they do not need protein carriers in the blood (albumin)

during fasting and starvation, ketone bodies are made when ____

acetyl CoA amount exceeds oxidative capacity (we are breaking down too many FAs) so the TCA cycle stops to allow gluconeogenesis to occur

using ketone bodies as an alternate energy source does what to glucose?

spares it

what is the rate limiting step of ketogenesis?

3 acetyl CoA for HMG CoA via HMG CoA synthase

_____ is derived non-enzymatically by spontaneous decarboxylation and may be detected as a “fruity breath odor”

acetone

since the liver lacks _____ it cannot use ketone bodies as energy (just make sit for the other tissues)

thiophorase

explain ketone bodies, type 1 diabetes/starvation

type 1 diabetes and starvation = no insulin

no insulin = will encourage the breakdown of fatty acids → too much breakdown leads to too much acetyl CoA → ketone bodies

remember insulin inhibits lipase, so if insulin is low then lipase can get the FAs out of storage