when are fatty acids synthesized
when carbohydrate (glucose) and protein (amino acid) levels are high
where does fatty acid biosynthesis occur
cytoplasm of most cells, w/ liver the most reactive
what happens to excess fatty acids in liver
exported as triglycerides packaged in very low density lipoproteins (VLDL) to adipose tissue, where they're stored
what metabolites does FA synthesis require
what elevates/decreases FA synthesis?
insulin: elevates FA synthesis
glucagon: decreases FA synthesis
in high glucose conditions, what are the steps that set up fatty acid synthesis in the cytosol?
high glugose => excess FA synthesis
glucose is metabolized by glycolysis, PDH to acetyl CoA
acetyl CoA enters TCA cycle, produces citrate
some of the citrate continues through TCA cycle to produce ATP for FA synthesis; some citrate leaves the mito on TCA carrier to the cyto, where it produces acetyl CoA
cytosolic acetyl CoA enters lipogenesis to produce palmitic acid
what happens to palmitate produced by fatty acid synthase?
1) used or store din the liver
2) transported as VLDL to adipose tissue, where it's stored
3) converted to longer chain fatty acids (like stearate, C18) by elongation enzymes or monounsaturated fatty acids (eg oleic acid) by desaturation enzymes
what happens to acetyol coA in the mito produced from glucose?
cannot leave the mito to become available in cyto for fatty acid biosynthesis
therefore must react w/ OAA to produce citrate which is transported out of mito via citrate shuttle
when does the citrate shuttle function/how
mito acetyl CoA cannot leave the mito, so:
mitochodnrial acetyl CoA reacts w/ OAA to produce citrate
citrate transported out of the mito via via the citrate shuttle, on the TCA carrier
citrate is leaved by citrate lyase, an ATP-dependent enzyme, to OAA + acetyl CoA
OAA is reduced to malate
malate 1) reenters the mito, oxidized by to OAA or 2) is oxidized in cyto by malic enzyme to produce NADPH for FA synthesis
how is OAA regenerated in the mito
from either Pyruvate via pyruvate carboxylase
or from malate
in the high energy state, what happens to glycolysis vs fatty acid synthesis? what enzymes does this impact?
glycolysis slows & fatty acid synthesis is stimulated in the high energy state
isocitrate DH slows
what is the rate limiting step of FA synthesis
acetyl coA carboxylase
describe the rate limiting step of FA synthesis
FA synthesis requires acetyl CoA and malonyl CoA
malonyl CoA is synthesized from acetyl CoA by acetyl CoA carboxylase, which is the rate limiting enzyme of FA synthesis
biotin is the cofactor for the carboxylation
what activates vs inhibits acetyl CoA carboxylase?
activators: citrate, insulin - which dephosphorylates it
inhibitors: palmitoyl CoA (product), AMP activated kinase, glucagon/cAMP-PKA
is acetyl coA carboxylase activated or inactivated when phosphorylated
inactive when phosphorylated - which is how AMP activated kinase, glucagon/cAMP-PKA inactivate it
what are sources of NADPH for fatty acid synthesis?
1) first step of the PPP pathway
2) malic enzyme under lipogenic conditions
describe how palmitate is formed?
acetyl CoA and malonyl CoA from the ACC reaction are transferred to the fatty acyl synthase (FAS) complex
acetyl CoA binds to a cysteine group of the condensing enzyme in teh FAS complex
malonyl CoA binds to the acyl carrier protein (ACP) of the FAS
ATP drives reaction of condensing enzyme making a 4C product from acetyl CoA and Malonyl CoA
This 4C intermediate + CO2 now are produced
the 4C acetyoacetyl CoA is then reduced, hydrated, and reduced again to produce a saturated 4C butyryl CoA
these steps require NADPH
butyryl CoA now repeats teh cycle: attachess cyteine SH of dondensing enzyme, condenses with malony CoA, reduces, hydration, reduction to produce a 6C fatty acid
ULTIMATELY: C16 palmitate is formed, which can't bind to the cysteine and is released from the FAS complex
how is palmitate aka palmitoyl coA used?
1) stored as triglycerides, esp in liver and adipose tissue
2) forms phospholipids needed for membranes
3) can be elongated to produce C18, C20 fatty acids
4) can be desaturated to produce unsaturated fatty acids
how does acetyl coa carboxylase regulate fatty acid synthesis
it is the rate limiting enzyme for formation of malonyl coa from acetyl coa
how do lipogenic conditions regulate fatty acid synthesis?
high glucose, genes for citrate cleavage enzyme, malic enzyme acetyl coA carobxylase, and FAS are activated by SREBP which itself is activated by insulin and inactivated by glucagon
how does malonyl CoA regulate fatty acid synthesis
malonyl CoA is needed for FA synthesis
it's a powerful inhibitor of acyl carnitine transferases which bring FA into mito for B-oxidation
so FA synthesis and oxidation don't occur at same time