Lipids Flashcards
energy storage, biological membranes, protein modification, signal transduction, and digestion of food
functions of lipids
- one polar end (carboxyl group) and a long hydrophobic tail (alkyl chain)
- humans usually have an even number of carbons (16-20)
structure of fatty acid
- 3 FAs esterfied to a glycerol
- very hydrophobic
triacylglyerol (TAG)
location of FA synthesis
cytoplasm
location of FA degradation
mitochondria
Human FA desaturases can only introduce double bonds where?
proximal half (up to carbon 9)
Essential FAs
Linoleic acid (omega 6)>>arachidonic acid Linolenic acid (omega 3)
Can TAG be transported?
No, it’s too hydrophobic. It must be broken down to FFAs first
What is the regulated step of FA degradation?
Carnitine-palmitoyltransferase I (CPT1)
Where does FA degradation occur?
mitochondria
What does FA break down to?
acetyl-CoA
produces CO2 and shortens FA chain by one carbon
alpha-oxidation
produces acetyl-CoA (2C’s)
beta-oxidation
ketone is made from…
acetyl-CoA
What reducing equivalents are made during FA degradation?
FADH2 and NADH
How is the degradation of unsaturated FA differ than that of saturated FA?
requires isomerases to move the double bonds until it looks like simple FA, then proceeds the same way via beta-oxidation
beta-oxidation in peroxisomes
occur in liver and kidney
minor fraction of FAs are degraded this way.
- H2O2 instead of FADH2
- degrades long chains down to 8 C’s
hypoglycemia with unusually low level of ketones in blood and urine
FA degradation disorder because it interferes with production of ketone bodies
Acute Fatty Liver of Pregnancy
long-chain hydroxyacyl-CoA dehydrogenase deficiency leading to accumulation of long chain FAs in liver. rare condition that can occur in pregnant women in the third trimester.
Non-ketotic Hypoglycemia
- FA import disorder (carnitine deficiency)
- Acyl-CoA Dehydrogenase Deficiencies (along with accumulation of FAs)
problems with alpha-oxidation of phytanic acid (branched-FA). patient presents with accumulation of phytanic acid in blood and tissues, also neurological defects
Refsum Disease
accumulation of long FAs (24-26Cs), plasmologen deficiency, myelination deficiency
Zellweger Syndrome - dysfunctional peroxisomes
In what organs does synthesis of ketone bodies occur?
liver and kidney
What is the regulated step in synthesis of ketone bodies?
HMG-CoA lyase
What intermediate of ketone body synthesis can also be part of cholesterol synthesis?
acetoacetyl-CoA
What enzyme is used by both synthesis of ketone bodies and cholesterol?
HMG-CoA synthase
What can’t the liver and kidney break down ketone bodies?
missing aceoacetate/succinyl-CoA transferase (catalyzes HMG-CoA»acetoacetyl-CoA)
How many molecules of acetyl-CoA does it take to make a ketone body?
two
high ketone concentrations
metabolic acidosis
What types of FAs are gluconeogenic?
odd number FAs: break down to 1 acetyl-CoA and 1 propinoyl-CoA (gluconeogenic)
How does acetyl-CoA get transported out to mitochondria?
citrate cleavage pathway
ATP-citrate lyase
citrate»acetyl-CoA+OAA using one ATP
What does high level of cytoplasmic citrate indicate?
CAC is not able to keep up with all the acetyl-CoA. Glycolysis slows and FA synthesis increases
In the reaction catalyzed by malic enzyme (malate»pyruvate), what else is produced?
NADPH
Regulated step of FA synthesis
Acetyl-CoA» Malonyl-CoA catalyzed by acetyl-CoA carboxylase
Where does FA synthesis occur in a cell?
cytosol
large multifunctional enzyme that catalyzes the synthesis of 16 carbon FA (palmitic acid) without releasing an intermediate
FA synthase
Both synthesis and elongation of FAs occur at which end of the molecule?
carboxyl-end
not omega end
Where in the cell does elongation of FAs occur?
either mitochondria or ER
In the ER, what is the carbon donor for elongation of FA?
malonyl-CoA (located outside the mitochondrial)
In the mitochondria, what is the carbon donor for elongation of FA?
acetyl-CoA (located inside the mitochondria)
Both elongation and desaturation of FA requires what?
NADPH
What does desaturation occur in the cell?
ER
Desaturation of FA uses what system?
p450 monoxygenase system
What does TAG synthesis require from glycolysis during well-fed state?
glycerol donor:
DHAP»Glycerol-3-Phosphate catalyzed by glycerol phosphate dehydrogenase
What is the committed step of TAG synthesis?
catalyzed by DGAT (acyl-CoA:diacylglycerol acyltransferases)
In the reverse of TAG synthesis (hydrolysis of TAG), what is the enzyme that catalyzes the reaction?
lipases
What does hydrolysis of TAG yield?
TAG+3H20»Glycerol+3FA
What induces the expression of acetyl-CoA carboxylase, FA synthase, malic enzyme and G6PD?
insulin
What do malic enzyme and G6PD have in common?
they both produce NADPH (important for FA synthesis)
What allosterically activate acetyl-CoA carboxylase and FA synthase?
citrate
The presence of malonyl-CoA inhibits what?
FA degradation
protein coat surrounding fat droplets
perilipin
hormone-sensitive lipase is active under what hormone?
glucagon
What transports FFAs in the circulation?
albumin
Why does TAG synthesis also occur during fasting state?
too much FFAs are released so the liver re-esterifies them back to TAG
synthesis of membrane lipids begins with the formation of …
diacylglycerol (DAG) from lgycerol phosphate and acyl-CoA
What enzyme catalyzes the rate-limiting step in the synthesis of phosphotidylcholine?
phosphocholine cytidyltransferase
What are the general reactions to membrane lipid synthesis (PC & PE)?
X is either choline or ethanolamine
1) activation by phosphorylation
2) transfer to CTP to make CDP-X
3) X transferred from CDP-X to DAG to make phosphotidyl-X
What enzyme is involved in the synthesis of phosphotidylserine? What reaction does it catalyze?
phosphotidylserine synthase
- exchanges ethanolamine from PE with serine
What enzyme is involved with the synthesis of phosphotidylinositol? What reaction does it catalyze?
phosphotidylinositol synthase
- CDP-DAG binds with inositol
How does the synthesis of PI differ than the synthesis of PE or PC?
CTP binds with DAG first, not the head group
helps with folding of mitochondrial ETS and buffers electrons in membranes
cardiolipin
outer leaflet membrane lipids
phosphotidylcholine (PC) and sphingomyelin
inner leaflet membrane lipids
phosphotidylethanolamine (PE)
phosphotidylserine (PS)
the transfer of this membrane lipid to the outer leaflet signals apoptosis
PS (phosphotidylserine)
functions to exchange FAs on membrane lipids
phospholipases
- phospholipase A1»C1
- phospholipase A2»C2
- phospholipase C»removes phosphate head from C3
What important signal transduction reaction does phospholipase C catalyzes?
PIP2»IP3+DAG
Which phospholipase produces the signaling molecules prostaglandin and thromboxane?
phospholipase A2
What essential acid is required for the synthesis of arachidonic acid?
Linoleic Acid
What are the steps to the synthesis of arachidonic acid?
1) elongation and desaturation of linoleic acid to make arachidonic acid
2) it gets incorporated into the phospholipid membrane until signal
3) upon stimulation, phospholipase A2 cleaves arachidonic acid from C2
What is the substrate in the synthesis of prostaglandins?
free arachidonic acid
What enzyme is involved with the synthesis of prostaglandins?
COX1/2 and Prostaglandin synthase
What enzyme is involved with the synthesis of thromboxanes?
thromboxane synthase
What enzyme is involved with the synthesis of leukotrienes?
lipoxygenase reaction
What can potentially inhibit the synthesis of leukotrienes?
corticosteroids (inhibits phospholipase A2)
lipoxygenase inhibitors
What can potentially inhibit the synthesis of prostaglandins?
corticosteroids (inhibits phospholipase A2)
aspirin or NSAIDs (inhibits COX1/2 and prostaglandin synthase)
cannot be stored and readily diffuses across membrane
prostaglandins
promotes smooth muscle contraction, involved with anahylaxis, asthma can be alleviated with the enzyme inhibitor
leukotrienes, lipoxygenase inhibitors
inflammatory processes - causes vasodilation
during delivery- contraction of uterus
blood - inhibits platelet aggregation
prostaglandins
condensation of leukotriene A4 with glutathione makes…
leukotriene C4
membrane lipid with fatty alcohol in ether-linkage
plasmalogens
induction of ether linkage in the synthesis of plasmalogens must occur where?
peroxisomes
1 FA, 1 polar head group on sphingosine (no glycerol)
sphingolipid
ceramide + phosphocholine
sphingomyelin
ceramide + glucose or galactose
cerebrosides
cerebrosides + sulfate group
sulfatide
ceramide + 2-4 neutral sugars
globosides
ceramide + negative charged NANA (N-acetyl neuraminic acid)
gangliosides
glycosphingolipids are found…
on the outside of the cell because they are glycosylated
genetic defects in any of the enzymes required to break down glycolipids will lead to accumulation of undegraded glycolipids in the lysosomes of phagocytic cells
sphingolipidoses
defect in the enzyme beta-glucosidase leading to accumulation of glucocerebroside, symptoms include liver and spleen enlargement, erosion of long bones
Gaucher Disease
defect in the enzyme beta-hexosaminidase A leading to accumulation of ganglioside GM2, symptoms include intellectual disability, blindness, cherry red spot on macula, death before age 3
Tay-Sachs Disease
Where does the synthesis of cholesterol occur (organs)?
liver, intestines, and reproductive tissues
What cell compartment does the synthesis of cholesterol occur?
cytosol
What is the rate-limiting step for the synthesis of cholesterol?
HMG-CoA reductase (HMG-CoA»Mevalonic Acid), takes 2 NADPH
- can be converted to dolichol-P
- used in prenylation of proteins
- precursor for synthesis of CoQ
Farnesyl PP
Regarding regulation of HMG CoA Reductase, what does the action of phosphorylation by AMP-dependent kinase do?
inactivates cholesterol synthesis
Regarding regulation of HMG CoA Reductase, what does insulin-dependent dephosphorylation do?
activates it thus cholesterol synthesis occurs when blood glucose increases
Regarding regulation of HMG CoA Reductase, what does the presence of cholesterol do?
end-product inhibition
hydrophilic surface and lipophilic core
lipoproteins
What enzyme catalyzes the esterification of cholesterol to make cholesteryl ester?
LCAT (lecitin:cholesterol acyltransferase)
found in hydrophobic center of lipoproteins or in cytoplasmic fat droplets
cholesteryl esters
Regarding the regulation of hormone-sensitive lipase (HSL), what does insulin do?
inhibits HSL - prevents release of FFA during well-fed state
Regarding the regulation of hormone-sensitive lipase (HSL), what does cortisol do?
induces HSL - increases release of FFA from adipose tissue
Regarding the regulation of hormone-sensitive lipase (HSL), what does glucagon do?
stimulates HSL and it’s mediated by cAMP and PKA
- acidic and water-soluble
- secreted by the liver through the bile duct into the digestive tract and are very effective in emulsifying fat from the diet
bile acids
cannot be degraded by human enzymes, must be excreted in the form of bile acids
cholesterol and its derivatives
- regulates entry
- activator of LCAT
- extract lipids from membranes
ApoA
structural proteins that give lipoproteins its structures
ApoB
ApoB100 - VLDL, ApoB48 - chylomicrons
- regulates the exit
- modulates function of lipoprotein lipase (LPL)
ApoC
- marks the surface to help mediate interactions with receptors
- removal of remnant particles
ApoE
secreted into the lymphatic system and enter blood through thoracic duct
chylomicrons
packed with TAGs synthesized by enterocytes from dietary fats
chylomicrons
functions to distribute dietary lipids throughout the body
chylomicrons
How do chylomicron remnants get removed?
- by the liver
- ApoB48 and ApoE on the remnants bind to LDL receptors on the surface of hepatocytes. This initiates receptor-mediated (clarthrin) endocytosis
function in reverse cholesterol transport from the peripheral tissues to the liver
HDL
delivers lipids made by the liver to peripheral tissues
VLDL
- leaves full and drop things off
leaves the liver empty and brings back cholesterol picked up from peripheral tissues
HDL (reverse cholesterol transport)
enzyme that transports cholesterol actively out of the cell membranes to HDL
ATP-binding Transporter A1 (ABCA-1 aka Cholesterol Efflux Regulatory Protein (CERP))
enzyme that esterfies cholesterol once it has been transferred into HDL
LCAT (lecitin:cholesterol acyltransferase)
liberates FFAs and glycerol from TAGs within the lipoproteins
lipoprotein lipase (LPL)
