Lipid Metabolism Flashcards
what is the major source of carbon for fatty acid synthesis?
dietary carbons
fatty acid synthesis overview
occurs in liver
secondarily in adipose, brain, kidneys, lactating mammary glands
requires coordination btwn cytosolic and mitochondrial rxns
precursor and end product of FA synthesis
acetyl coA 2C
palmitic acid 16C
list the 3 phases of fatty acid synthesis
- cytosolic entry of acetyl coA
- –made in mito matrix but needed in cytoplasm - generation of malonyl coA
- –acetyl coa is carboxylated to malonyl coA
- –most important substrate in FA synthesis
- –***rate limiting rxn - fatty acid chain formation
- –FA synthase catalyzes 7 rxns to incorporate acetyl coa and malonyl coa into palmitate
list the first 4 steps in FA synthesis
- condensation of acetyl coa w/ oxaloacetate = citrate
- –citrate synthase - transport of citrate from mito to cytosol
- –via citrate lyase - citrate converted back to acetyl coa and OAA
- –citrate lyase
- –acetyl coa can now be used for FA synthesis in cytosol - OAA reduced to malate
- –malate dehydrogenase
steps 5 and 6 of FA synthesis
- malate transported into mito via malate a-ketoglutarate transporter
- –oxidized to OAA
- –malate dehydrogenase - cytosolic malate converted to pyruvate
—malic enzyme
pyruvate transported to mito via pyruvate transporter
—carboxylated to OAA by pyruvate carboxylase
presence of citrate and insulin will ______ FA synthesis while glucagon, epinh, high [AMP], palmitate, PUFA will ______ synthesis
increase
decrease
conversion of acetyl CoA to malonyl CoA by carboxylation
catalyzed by acetyl coa carboxylase ACC
**rate limiting enzyme of fatty acid synthesis
ACC adds CO2 to acetyl coa
- -uses ATP
- –uses biotin as cofactor
malonyl CoA
regulator — inhibits carnitine acyltransferase
**rate limiting step in FA degradation
prevents FA synthesis and degradation from occurring simultaneously
regulators of phase 3 in FA synthesis
promoters:
insulin
glucocorticoid hrs
inhibitory
PUFA
describe FA chain formation
2 C from malonyl coa are sequentially added to growing FA chain
- –occurs in 7 rxns
- –forming palmitate (16:0)
these rxns occur on FA synthase complex (FAS complex)
FAS
multi-enzyme complex
composed of 2 dimers arranged head to tail
each has 7 enzyme activities
an acyl carrier protein ACP
palmitate synthesis
1 acetyl coa + 7 malonyl coa + 14 NADPH + 14 H+
CH3(CH2)14COO- + 14 NADP+ + 8 CoA + 6H20
what is the purpose of reduction rxns in the FAS reactions?
using dehydration of NADPH to remove double bonds
creating a fully saturated growing FA
what are the sources of NADPH?
malic enzyme = 1
PPP = 2-12
list the 7 rxns in FA synthesis for creating palmitate
- acetyl ACP
- malonyl ACP
- –condensation - acetoacetyl ACP
- –reduction - D-3 hydroxbutyryl ACP
- –dehydration - crotonyl ACP
- –reduction - butyryl ACP
- palmitate
occurs 7x total = C16
list the main rxns of the 3 phases in FA synthesis
- ATP citrate lyase
citrate —> acetyl coa + OAA - acetyl coa carboxylase
**rate limiting step
acetyl coa + CO2 —> malonyl coa - FA synthase
4C FA - repetition —> 16C palmitate
regulation of ATP citrate lyase
stimed by phosphorylation
gene expression induced by glucose/insulin
gene expression inhibited by:
PUFA
leptin
PUFA
polyunsaturated FAs
regulation of acetyl CoA carboxylase
inactive dimer – active polymer
- allosteric regulation
- phosphorylation/De-phos
- induction
allosteric regulation of acetyl coa carboxylase
citrate +
long chain FA/palmitate -
phosphorylation control of acetyl coa carboxylase
phos = +
insulin
de-phos = -
epinh
glucagon
AMP
control of gene expression induction - acetyl coa carboxylase
gene exp up regulated by high carb/low fat diet
regulation of FAS
allosteric reg — presence of phosphorylated sugars increases activity
gene expression control:
+ = insulin, glucocorticoid hrs, high carb/low fat diet
- = high fat diet, starvation, PUFA
synthesis of longer chain FA
elongation of palmitate
occurs in SER or mito
occurs 2C at a time
NADPH has reducing power
brain cells need longer FA chains C18-24
carbon donors for longer chain FA synthesis
SER uses malonyl coa
mito uses acetyl coa
desaturation of FAs
inducing double bonds
occurs in SER catalyzed by acyl coa desaturases
humans can add DB btwn carbons: 4-5, 5-6, 6-7, 9-10
but humans cannot make 9-10 DBs must ingest thru diet as omega 3/6 FAs
essential fatty acids
humans cannot make w-3 or w-6 FAs
must ingest their precursors as:
linoleic acid
linolenic acid
nomenclature of FAs
based on position of carbon from methyl end = omega end
6C away from methyl = w-6
what is the importance of not being able to create DBs between the 9-10 carbons?
these fatty acids are very important for development and functioning
ex. EPA and DHA
eicosanoid hormones
arachidonate
FA derived from linoleate
major precursor for signal molecules
prostaglandin
yields 9 major classes of prostaglandins called PGA to PGI
describe eicosanoid hormones
local short lived hormones
influencing activities of cells inflammation blood flow ion transport synaptic transmission induce sleep
clinical example of eicosanoid hormone
aspirin blocks enzyme that converts arachidonate into prostaglandin
blocking this step interferes w/ signaling pathways
such as: inflam, fever, pain, blood clotting
major storage form of FAs
triacylglycerol or TAG
have almost 7x more nrg than carbs
a glycerol head
3 FA chains attached
sources of TAGs
diet
processed in intestines
hepatocytes and adipocytes
perilipin
family of proteins that coat lipid droplets in adipose and muscle cells
regulate lipolysis by controlling physical access to TAGs
are regulated by PKA
overexpression of perilipin1 inhibits lipolysis
KO peilipin increases it **used for obesity treatment
first phase of FA activation
occurs in cytosol
need to get FA into mito but the memb is not permeable to FAs
acyl-coa synthetase traps FA in cells
—making it metabolically active
translocation to mito matrix
carnitine converted to acyl carnitine
- –which can be moved into mito
- –via carnitine acyltransferase II
acyl carnitine can be converted back to carnitine in mito
—via carnitine acyltransferase II
4 steps of B-oxidation
- oxidation
acyl coa dehydrogenase - hydration
enoyl coa hydratase - oxidation
3-hydroxyacyl coa dehydrogenase - thiolysis
acetyl coa acetyltransferase
**these steps are repeated until FA broken down into acetyl coa
the 4 main steps of B-oxidation generate?
FADH2 (14)
—delivers e- to ETC
NADH (21)
—delivers e- to ETC
acetyl coa (96) ---enters TCA cycle
14+21+96 = 131
2 ATP used
= 129 net ATP
ketone bodies
water soluble, acidic compounds
- acetoacetate
- B-hydroxybutyrate
- acetone
produced in liver only
provide nrg for tissues and brain during fasting/starvation
utilization of acetoacetate
acetoacetate to acetoacetyl coa
—coa transferase
to 2 acetyl coa
—thiolase
