Fatty Acid: Synthesis & Storage Flashcards
where does fatty acid synthesis take place
cytosol
for synthesis of fatty acids, where does it obtain the carbons for it
shuttled from mitochondria via citrate
triacylglycerol synthesis is regulated by
insulin
if there is a lack of insulin (diabetes), what does it result in regarding fatty acid synthesis
increased lipolysis
increased fatty acid oxidation
failure to synthesize fatty acids
draw out the pathway of how insulin influences fatty acid synthesis and what direction it goes without insulingp
pg 5
what is the primary FA factory
hepatocyte
in FA synthesis how much ATP is contained in each acetyl CoA unit
10
besides liver, what else participates in FA synthesis
adipocyte
skin
glycolysis provides what 2 essential compounds for lipogenesis
Dihydroxyacetone-P
Pyruvate
what is a major carbon source for lipogenesis
glucose
what is function of Dihydroxyacetone-P
this becomes the scaffold that receives 3 fatty acids & becomes triacylglycerol – also TAG
what is function of pyruvate in lipogenesis
after conversion to acetyl-CoA and citrate – provides building blocks for fatty acid synthase in the cytosol
Acetyl CoA is shuttled from mitochondria to cytosol via
citrate
what is Acetyl CoA produced from
AA’s or carbohydrate
what breaks down citrate in cytosol
ATP-Citrate lyase
draw out pathway of citrate leaving and entering mitochodnria/cytosol
pg 7
pyruvate is decarboxylated to create
Acetyl CoA
pyruvate is diverted and carboxylated to produce
pyruvate carboxylase
Acetyl CoA + OAA with citrate synthase =
citrate
cell’s high energy charge inhibits
Isocitrate dehydrogenase
if Isocitrate dehydrogenase is inhibited, what happens
citrate accumulates and is exported via citrate shuttle
draw out the “balancing act” of forming citrate in mitochondria from pyruvate
pg 8
why is ATP needed for citrate lyase to break citrate into acetyl CoA & OAA
citrate is stable & energy needed to break bonds
pyruvate recycling produces add’l
NADPH
if there is insulin and enough energy you will produce
fat
what pathway is needed to produce fat
PPP (pentose phosphate pathway)
what is rate limiting step of fatty acid synthesis
ACC (acetyl CoA Carboxylase)
what enzymes require biotin
ACC
pyruvate carboxylase
propinyl coA
prostaglands are
hormones
prostaglands require
fatty acid
what kind of fatty acid do we need from diet
omega 6
to accumulate citrate have to stop or slow down
TCA cycle
How many carbons in Lauric acid
12 and 0 unsaturated
how many carbons in Myristic acid
14 and 0 unsaturated
how many carbons in Palmitic acid
16 and 0 unsaturated
how many carbons in Stearic acid
18 and 0 unsaturated
what are the two main ways NADH is produced
PPP
malic enzyme
describe how PPP makes NADH
The oxidative component of the pentose phosphate pathway two dehydrogenases allows the production of NADPH
describe how malic enzyme makes NADH
Malic enzyme recycles malate into pyruvate and in the process produces NADPH
production of NADPH is essentia for
fatty acid biosynthesis
what are the two dehydrogenases in PPP that produce NADPH
glucose 6 phosphate dehydrogenase and 6-phopogluconate dehydrogenase
what is a three carbon intermediate of acetyl coA
malonyl CoA
when enzyme is needed for acetyl coA → malonyl coA
Acetyl-CoA carboxylase
carboxylation requires
biotin
biotin deficiency has what symptoms
gastrointestinal upset, dermatitis, alopecia, paraesthesia and muscleache.
what is the major regulatory step to produce fatty acids
acetyl coa → malonyl coa
acetyl coa → malonyl reaction, what is needed
biotin
CO2
ATP
what are the 4 enzymes that require biotin
propionyl coenzyme A (CoA) carboxylase (PCC), pyruvate carboxylase (PC), β-methylcrotonyl CoA carboxylase (β-MCC), and acetyl CoA carboxylase (ACC).
what interfere with ingestion of biotin
avidin
where is avidin found
raw egg whites
what is allosteric activatory of acetyl CoA carboxylase?
citrate
what is allosteric inhibitor of acetyl CoA carboxylase?
palmitoyl CoA
how does citrate promote activity of acetyl coA carboxylase
induction of polymerization and gene expression
how does Palmitoyl-CoA inhibit activity of acetyl CoA carboxylase?
inhibits activity and induction via promoting depolymerization
what does by AMP-protein kinase (AMPK) do to acetyl coA carboxylase
inactivates
how does AMP protein kinase inactivate Acetyl CoA carboxylase
phosphorylation
with high levels of ATP what happens to acetyl CoA Carboxylase
Dephosphorylation, activated
describe the structure of fatty acid synthase
solid-state dimer of two multi-function monomers
symmetrical
Acyl carrier protein’s function holds growing acyl group with what bond?
thioester bond
with how many carbons does fatty acyl chain grow
2
how many carbons is palmitate acid
16
what donates carbons for growing chain of fatty acid
activated malonate
draw comparison of oxidative degradation & FA synthesis
pg 16
there is no free intracellullar palmitate, it exsits as
palmitoyl-CoA
what inhibits translocation of fatty acids to mitochondria
malonyl CoA
when lipogenesis is happening what does malonyl CoA do to ß oxidation
shut it down
where are FA elongated
ER
what is carbon source for FA elongation
malonyl CoA
what is used for reducing power for FA elongation
NADPH
what is the major difference b/w elongation of fatty acids and synthesis
in elongation: growing acyl chain is joined by thioester bonds to CoASH instead of ACP
what are two fatty acids we cannot synthesize
18:2 linoleic (Ω-6) and& 18:3 linolenic (Ω-3)
mammals cannot insert double bonds beyond what point
C9-10
draw out the Desaturation of a fatty acid by fatty acyl-CoA desaturase
pg 21
where does desaturation of FA take place
lumenal side of smooth ER
describe characterisitc of cytochrome P450 enzymes
located in themembrane endoplasmic reticulum and uses NADPH and O2.
fatty acyl-CoA desaturase is a member of what family
cytochrome P450
linoleic acid gives rise to
arachidonic acid
what is a vital component in the water barrier in skin
ceramide
in making a FA, after a desaturation then what
elongation of 2 Cs then another desaturation
arachidonic acid is needed as a major component of
water barrier in skin
what does PUFA stand for
polyunsaturated fatty acids
essential fatty acids are
Ω-3 and Ω-6
what is Ω-3
linolenic acid
what is Ω-6
linoeic acid
what is Alpha(α)-linolenic acid converted to
eicosapentaenoic acid & docosahexaenoic acid
the final step in docosahexaenoic acid synthesis is
peroxisomal β-oxidation to remove the 2-carbon acetyl-CoA from the 24:6 fatty acid called tetracosahexaenoic acid
what enzymes allow alpha linoleic acid to convert to EPA & DHA?
microsomal ER enzymes
what cells synthesize triglycerides
basically all of them
what activate free FA
CoASH
TAG stands for
triacylglyceride
TAG synthesis usually begins with
glycerol
what is first step to make TAG
glycerol phoshporylated
what enzyme phoshporylates glycerol in first step to make TAG
glycerol kinase
after glycerol is phosphorylated, what happens in TAG synthesis
activated fatty acids serve as substrates for fatty acid addition
in adipose tissue there is no expression of
glycerol kinase
since there isn’t glycerol kinase in adipose tissue, what is used to make Tag
DHAP (from glycolysis)
draw pathway for TAG synthesis in other tissues, adipocytes, and intestinal enterocytes
pg 24
insulin stimulates conversion of excess glucose to
glycogen & TAG
what does VLDL stand for
very long density lipopotrein
what enzyme is needed to breakdown TAG
lipoprotein lipase
during fasting, TAGs assembled in liver are loaded into
VLDL particles
where does VLDL assembly begin
RER
what does APO B-100 do
assembles core of phospholipids
mediate TG delivery at specific tissue destinations
VLDL is seceted into blood for what purpose
tissues have access to cholesterol and fatty acids
LPL stands for
lipoprotein Lipase
LPL is attached to
capillary wall
what activates LPL
apoprotein CII
what inhibits LPL
Apo CIII
TAG’s are hydrolyzed by
LPL
inside cells fatty acids are activated with
CoASH
what happens to FA to store them as TAGs
esterified
what is the difference b/w VLDL & chylomicrons?
chylomicrons comes from the lipids in the diet, that cholesterol and TAGs while VLFL are TAGS and cholesterol produced by the liver.
so basically chylomicrons = diet
VLDL = we make it
what holds LPL to capillary wall
heparan sulfate tether
LPL requires activation by
Apoprotein CII
how does NADH production make sense? how does it help us?
needed to fuel fatty acid biosynthesis
describe acetyl coa regulation
acetyl coA needs to accumulate but not so much to inhibit pyruvate DH
needs careful regulation
biotin deficiency symptoms related to
fatty acid synthesis
propionyl coA
propionyl coA is important for the
brain
what does enzyme do to acetyl coA carboxylase
activates by dephosphorylating
acetyl coa carboxylase when it is monomer vs polymer when is it active vs. inactive
monomer: inactive
polymer: active
FAS monomers contain covalently bound
phosphopantotheine
phosphopantotheine is what
vitamin
phosphopantotheine is bound to what residuc of ACP on FAS (fatty acid synthase)
serine
phosphopantotheine is attached to the FAS protein itself via
serine
tRNA occupies t and a site. on a site have free amino group b/c using carboxylic group. amino group nucleophilic attack that will attack ester bond in t site to form peptide bond. moves to a site and become t site (not sure if he is saying t or p)
first is terminal last one removed is ???
help
ACP site and cysteine site
moved from ACP to other site ???? pg 14
FA biosynthesis and ß oxidation
are similar, basically just opposite
Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH + 14 H+yields
Palmitate + 7 CO2 + 14 NADP+ + 8 CoASH;
add 8 ATP (for citrate lyase)
Palmitate + 7 CO2 + 14 NADP+ + 8 CoASH;
add 8 ATP (for citrate lyase) comes from
Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH + 14 H+yields
The cytosolic produced 16 carbons, palmitoyl CoA is translocated to the ER so elongase enzyme activity extends it to 18 carbon units called
estearic acid.
draw out Oxaloacetate & acetyl coa crossing cytosol
pg 9
look at sequence of events during synthesis of fatty acid
pg 14
omega 6 in diet comes in what form
linoelic acid (omega 6)
desaturase is located where
ER
ALA stands for
Alpha(α)-linolenic acid
VLDL is from liver and equivalent to
chylomicron
protein in chylomicron to help is
Apoprotein B 48
protein in VLDL to help is
Apoprotein B 100
VLDL is source of
LDL
LDL comes from
VLDL
chylomicrons are present in what state
well fed
VLDL are present in what state
fasting
Apo CIII is
inhibitor of lipoprotein lipase
pts whoh ave GOF of Apo CIII what happens
packing of LPL is inhibited. it interferes with assembly of triacylglycerides in VLDL and it goes back to liver and they start to get liver problems and have fatty liver which is precursor to diabetes type II
how is glucose trapped and controlled in liver without insulin signaling (how do we control glucokinase?)
glucokinase is trapped in the nuclei
write out the comparison/contrast of synthesis and degradation & understand
pg 17
when adipocytes are too big what happens
they attract attention of marophages which interfere with insulin signaling
what is the initial acceptor of fatty acids during TAG synthesis?
Glycerol-3-phosphate
during the well fed state what do liver and adipoctyes use to produce glycerol-3-phosphate
glycolysis intermediate: dihydroacetone phosphate (DHAP)
the liver contains glycerol kinase, what does this enzyme do
phosphorylate glycerol and produce glycerol-3-phospahte
in glycerol, position 2 has what kind of fatty acid
unsaturated
what process is used by adipocytes to form TAGs
Glyceroneogenesis
what stimulates lipolysis
glucagon & EPI
during lipolysis what is inhibited
glycolysis
Glyceroneogenesis is essentially an abbreviated version of
gluconeogenesis
glycerol 3-phosphate is needed for synthesis of
triacylglycerol
draw pathway for Glyceroneogenesis
pg 29
about 75% of FA released by lipolysis, what happens to it
resterfied to reform TAGs instead of being used for fuel
what regulates the levels of PEP carboxykinase
cortisol
how does liver send TAG to blood?
in VLDL
what is the “Leash” of FA release
insulin
if insulin is weak or not working correctly what hapens to FA release
insulin is the “leash” so glucagon has a higher role and FA is released at higher rate/amount
what does FOX01 do
TF that controls gluconeogenesis in genes
what is the result of insulin on SREBP’s
insulin activates them - they are very sensitive to insulin
draw the pathway of insulin affect on SREBP-1c
bottom right pg 31
draw the effect of insulin and glucose on different TF
pg 31 left side
describe how hyperinsulemia precedes diabetes
an obese person before they are diabetic will have increased insulin resistance. this will continue until eventually their pancreas cannot keep up with demand, and then insulin levels will drop and they will have hyperglycemia
what does insulin do to activate glycogen synthesis
it activates glycogen synthase via Akt2
what does insulin do to decrease gluconeogenesis?
inactivates FOX01
what promotes activation of SREBP1
insulin signaling
what activates ChREBP
liver when metabolized
SREBP1 and ChREBP both promote
de novo lypogenesis
what does insulin do to adipose tissue
inhibits lipolysis & promotes glucose uptake
if there is more glucose entering the cell what pathway will be increased
PPP
If PPP pathway is increased (too much glucose entering) then what is there increased levels of
xylulose-5-phosphate
xylulose-5-phosphate does what to ChREBP
it activates PP2Aδ which will then remove the inhibitory phosphorylations on ChREBP in cytosol and nucleus
ativation of LXRα results in
increased expression of ChREBP in liver
draw out ChREBP pathway and its role in lipid & glucose homeostasis
pg 34
draw out and explain the main mechanisms of insulin resistance
pg 35
Increased intracellular diacyglycerols lead to activation of
PKC-θ and PKC-ε in skeletal muscle and liver (respectively)
activation of PKC-θ in muscle will lead to
decreased muscle glycogen synthesis, owing to reduced insulin-stimulated GLUT4 translocation to the plasma membrane.
GLUT4 won’t work as well so more glucose in blooddraw
activation of PKC-ε in liver will lead to
decreased hepatic glycogen synthesis, owing to decreased activation of glycogen synthase, and increased hepatic gluconeogenesis
draw out basic cellular insulin resistance in muscle
pg 36
draw out basic cellular insulin resistance in liver
pg 36
draw insulin receptor with insulin sensitivy and insulin resistant
pg 37
draw insulin receptor pathway
pg 37
draw insulin sensitive liver
pg 38
draw insulin resistant/type II diabetes liver
pg 38
draw prediabetes liver
pg 38
draw type II diabetes liver
pg 38
review concept key
pg 39
