1
Q
what are lipids?
A
heterogeneous group of biological compounds, including fats, oils, steroids, waxes, that are relatively insoluble in water
2
Q
what are common properties of lipids?
A
- relatively insoluble in water
- soluble in nonpolar solvents
3
Q
what are the functions of lipids?
A
- energy storage
- important dietary components because of their high energy
- structural components of biomembranes
- serve as thermal insulators in subcutaneous tissues and around certain organs
- signaling molecules
- hormone precursors
4
Q
what are some clinical consequences of dyslipidemias?
A
- tend to accumulate in joints
- atherosclerosis, which can lead to stroke and heart attack
5
Q
what are the different types of dietary lipids?
A
- purifies lipids: triacylglycerols – neutral lipids (completely hydrophobic)
- cellular lipids: lipid droplets (triacylglycerols, cholesterol esters), and membrane lipids (phospholipids, cholesterol, glycolipids)
5
Q
how are dietary lipids absorbed (path from liver to small intestine)?
A
- liver generates bile salts, which generate micelles
-when in small intestines, pancreatic lipase hydrolyzes the triacylglycerols into free fatty acids and monoglycerides - i-FABP carries fatty acids inside the enterocytes, where they are converted back into triacylglycerols
6
Q
how are dietary lipids transported from the enterocyte into the circulation?
A
the fatty acids and MAG are converted into triacylglycerols then packaged into chylomicrons, where they can be secreted into the circulation
7
Q
where are free fatty acids located?
A
mitochondrion and cytosol
8
Q
what is the structure of a fatty acid?
A
- carboxylic acid with a long hydrocarbon chain
9
Q
what is the difference between saturated and unsaturated fatty acids?
A
- saturated: all carbon bonds are single bonds
- unsaturated: has at least 1 double bond
10
Q
which has a higher melting point, cis-unsaturated or trans-unsaturated?
A
cis
11
Q
how is melting point affected by saturated and unsaturated FAs?
A
- satur: longer has higher melting point
- unsat: more unsaturation lowers melting point
12
Q
how are branched FAs different from other types?
A
- undergoes alpha-oxidation (peroxisome) instead of beta-oxidation (mitochondria)
13
Q
what is the structure of triacylglycerols? how are they stored?
A
- 3 acyl chains with 1 glycerol (100% hydrophobic)
- in vesicles
14
Q
what is the structure of phospholipids? how are they stored?
A
- glycerol/sphingosine with 3 acyl chains
- part of the membrane
15
Q
how are endogenous TGs transported into the blood?
A
by VLDL
16
Q
where are TGs located?
A
lipid storage droplets
17
Q
what are the steps of TGs to energy (exogenous and endogenous)?
A
exo:
1. synthesized
endo:
1. ingested
2. transported
3. stored
4. mobilized to generate energy
18
Q
Explain lipolysis in the GI-tract. (Enzyme used, when it occurs, regulation)
A
- occurs in fed state
- pancreatic lipase breaks down TGs
- regulated by substrate availability
19
Q
How can a charged FA traverse the non-polar membrane bilayer?
A
- Diffusion
- Transport
- Acidification of Pinochet of vesicle (extra cellular fluid has pH~7 so FA in charged state, internalized Pinochet if vesicle has pH~5 so FA neutral, FA can now diffuse across membrane, and cytoplasm has pH~7 so FA back to charged state)
20
Q
Explain lipolysis in blood vessels (when it occurs, enzyme, regulation).
A
- occurs in fed state
- lipoprotein lipase breaks down TGs into FAs
- LPL coats endothelial cells
21
Q
What are the differences between the lipid droplets in the adipocyte and the liver?
A
- adipocyte function is to store large amounts of TGs as fat droplets, so almost fills cell
- liver has much smaller lipid droplets and serve as transient buffer reservoir of esterified FAs and esterified cholesterol
22
Q
Explain lipolysis in lipid droplets (when it occurs, enzyme, regulation).
A
- occurs when fasting or during exercise
- 3 enzymes: TAG to DAG by ATGL, DAG to MAG by HSL, MAG to glycerol by MGL
- the FAs released either go to blood (bounded by albumin), go to target or used immediately
- regulation: hormonal regulation - PKA (activated by adrenaline) phosphorylates perilipin (coats droplets) and HSL which activates the pathway
23
Q
Where does lipogenesis occur?
A
In enterocyte (liver)
24
Explain lipogenesis in enterocyte.
- a fatty acid is activated by CoA via Acyl-CoA synthase, which makes a high energy intermediate Acyl-CoA
- in process there is inorganic pyrophosphatase activity, which drives the reaction
- we then take 2-monoacylglycerol (from diet) and we can then add the Acyl-CoA to make DAG
- can then add another Acyl-CoA to make TAG
25
How is lipogenesis in enterocyte regulated?
Substrate availability
26
Where does TAG de novo synthesis occur?
In lipid droplets in liver and adipose
27
Explain TAG de novo synthesis.
- glycerol-3-phosphate generated by PPP pathway ( so either DHAP to glycerol-3-P or glycerol to glycerol-3-P — 2nd can only occur in liver)
- addition of 2 acyl-CoAs to make phosphatidic acid
- dephosphorylation by lipin makes DAG
- addition of 1 acyl-CoA makes TAG
28
How is lipogenesis regulated?
By insulin via transcriptional control
29
What happens in fed state?
1. Lipolysis (pancreatic lipase)
2. Re-assembly
3. Transport (via chylomicrons)
4. Lipolysis (LPL)
5. Lipogenesis (in lipid droplets)
30
What happens in fasting or excessive state?
1. Lipolysis (in lipid droplets)
2. Transport (via albumin binding)
3. Uptake in tissue
4. Beta-oxidation (makes ATP)
31
what are the different membrane lipids?
- glycerolphospholipids
- sphingolipid
- glycolipids
- sterols
32
what are the differences between glycerophospholipids and sphingolipids?
- glyc: FAs bound to phosphate group by glycerol, type of FAs may change
- sphi: FA bound to phosphate by amide, FA always the same
33
what are the role of membrane lipids?
- in/out symmetry
- microdomains (RAFTs are thick and stiff and non-rafts are thin and fluid)
- signaling (e.g. PI)
34
where does phospholipid synthesis occur?
ER
35
how are PI, PG, and cardiolipin synthesized?
- activation of phosphatidic acid by CDP-diacylglycerol synthase to make CDP-diacylglycerol (pyrophosphatase activity drives reaction)
- addition of inositol for PI, or glycerol 3-P for PG and cardiolipin
36
how are PE and PC synthesized?
- prime head group (either choline or ethanolamine) with ATP (addition of P)
- activating the head group by CTP (pyrophosphatase activity drives reaction)
- addition of DAG
37
how is PE converted to PC and where does this occur?
- occurs in liver
- get methyl groups from "one-carbon pathway"
- addition of 3 methyl groups to N of PE to make PC by PEMT
38
what is the one carbon pathway?
- ATP added to methionine (pyrophosphate released)
- makes 5-adenosyl-methionine, which has a sulfonium that is unstable to likely to release methyl group
39
which function is highly dependent on abundant PC production and what happens if there isn't enough?
- synthesis of bile
- gallstones
40
how is PS synthesized?
- transferase removes ethylamine and adds serine to make PS
- is reversible reaction, so decarboxylase can re-make PE
41
how are sphingolipids synthesized?
- addition of an activated acyl to the serine backbone (makes ceramide)
- transferring a phosphocholine head group to make sphingomyelin
- OR addition of glucose head group to make glycosphingolipid
42
where are phospholipases located?
plasma membrane
43
what are the roles of phospholipases?
cleave phospholipids to:
- generate signaling molecules
- convert phospholipids to another
- modulate the shape of the plasma membrane (production of monoacylchain phospholipids, which have a cone shape)
44
where does beta-oxidation occur?
mitochondria
45
where do FAs come from (for FA breakdown)?
- uptake from circulation
- lipolysis
- phospholipases (PLA)
46
how are FAs transported into the mitochondria?
1. FAs are activated by CoA via Acyl-CoA synthase (pyrophosphate activity)
2. coupling to Carnitine via Carnitine palmitoyl transferase I (CPT I)
3. transit toward the mitochondrial matric via carnitine/acylcarnitine translocase (so carnitine regenerated)
4. FA released into the matrix via carnitine palmitoyl transferase II (CPT II)
47
what is the rate-limiting step/enzyme of FA breakdown? how is it regulated?
- CPT I
- inhibited by malonyl-CoA since high concentration means high-energy state and need to activate FA biosynthesis
48
explain beta-oxidation of saturated FAs? what are the products?
- dehydrogenation (makes double bond between two CHs after COOH)
- hydration (addition of OH)
- dehydrogenation (makes C=O)
- thiolic cleavage (removes the end - makes acetyl-coA)
- repeat
- each cycle (removal of 2 carbons) makes: 1 FADH2, 1 NADH, 1 acetyl-coA
49
explain beta-oxidation of unsaturated FAs. what are the products?
- the saturated portion broken down like normal
for the unsaturations:
- isomerization (moves double bond to two CHs next to COOH)
- hydration (addition of OH)
- dehydrogenation (makes C=O)
- thiolic cleavage (removes the end - makes acetyl-coA)
- repeat
- each cycle (removal of 2 Cs) makes: 1 NADH, 1 acetyl-coA (no FADH2 produced)
50
explain beta-oxidation for polyunsaturated FAs (even and odd). What are the products?
- odd unsaturation: same as mono-unsaturation (no FADH2 produced)
- even unsaturation: FADH2 produced but costs 1 NADPH
- both produce 1 NADH and 1 acetyl-coA
51
explain beta-oxidation of odd-chain FAs.
- normal until the last 3 carbons
- last 3 released as propionyl-CoA
- propionyl-CoA converted to succinyl-CoA
- succinyl-CoA joins the CAC
52
explain beta-oxidation of branched FAs.
- normal for unbranched carbons
- branched carbons released as propionyl-CoA (which is converted to succinyl-CoA)
53
where does ketogenesis occur?
liver
54
when and why does ketogenesis occur?
occurs when:
- during fasting or starvation
- oxaloacetate is depleted (CAC stops)
why:
- ketone bodies serve as a shuttle for acetyl-CoA, which can be used by other tissues (like brain and heart) to make acetyl-CoA for energy
55
explain ketogenesis.
- 2 acetyl-coAs releases 1 acetate
- rest converted to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) intermediate
- then converted to acetoacetate, which can be converted to acetone or hydroxybutyrate
56
where does FA synthesis occur?
cytosol
57
how is acetyl-coA transported to the cytosol?
by citrate shuttle:
- acetyl-coA converted by citrate by citrate synthase (CAC)
- citrate can go to cytosol
- citrate lyase converts it back to acetyl-CoA (which also regenerates oxaloacetate)
58
explain FA synthesis. what is the rate limiting step?
1. Acetyl-CoA converted to malonyl-CoA by acetyl-CoA Carboxylase (ACC), which is a irreversible, rate-limiting step of the synthesis. (ATP breakdown provides energy)
2. Malonyl/Acetyl-CoA Transacylase (MAT) couples acetyl-CoA and malonyl-CoA with ACP, which keeps them activated (and prevents leakage to other compartments) -- "priming"
3. Elongation: "primed" acetyl/malonyl-CoA bound together (requires 2 NADPH) by fatty acid synthase -- addition of 2 carbons (malonyl-CoA keeps adding on) -- cycles until it is long enough and ACP is released
59
how much energy is needed to make FAs?
for addition of every 2 carbons need:
- 1 acetyl-CoA
- 2 NADPH
- 1 ATP
- also there is an extra 1 acetyl-CoA that is needed to start the synthesis
60
how is ACC (acetyl-CoA carboxylase) regulated?
allosteric:
- activated by citrate
- inhibited by FAs
Hormonal:
- insulin: stimulates glucose uptake and PDH (so more acetyl-CoAs produced)
- glucagon: inhibits (by PKA-mediated phosphorylation)
61
how are desaturations made in FAs?
by desaturases (there are 4 different ones that exists in mammals)
62
what is a lipoprotein?
a circulating lipid carrier composed of a neutral lipid core, a monolayer of polar surface proteins (phospholipids and cholesterol), and at least one apolipoprotein
63
what are the different lipoproteins?
- chylomicrons
- VLDL
- IDL
- LDL
- HDL
64
what are apolipoproteins?
amphipathic proteins that insert in lipoproteins and serve as ligand for lipoproteins recognition and docking
65
chylomicrons: when are they produced, what are the apo-proteins, how are they metabolized, and what are the target tissues?
- produced from dietary lipids
- ApoC, ApoE, ApoB-48
- when go in bloodstream, ApoC bind LPL, which breakdown down TAGs into FAs, and the remnants make chylomicron remnant, which has no ApoC
- FAs go to muscle and adispose
- chylomicron remnant bind to liver through recognition of ApoE and Apob-48, where it is internalized and broken down (liver can then make bile acids and use cholesterol for other things)
66
VLDL: where and why are they produced, what are the apo-proteins, how are they metabolized, and what are the target tissues?
- produced by liver with the excess lipids that it receives from chylomicrons, acts as a vehicle to deliver lipids to adipose
- have ApoC and ApoB100
- when go in bloodstream, ApoC bind LPL, which breakdown down TAGs into FAs, and the remnants make IDL (FAs go to muscle and adipose)
- IDL can either bind to liver or gets broken down into LDL by hepatic lipase
67
LDL: how is it made, what is its role, what is its target tissue.
- made by hepatic lipase acting on IDL
- role is to carry cholesterol esters to target tissue
- can go to liver but mostly peripheral tissue by ApoB100 receptor, which uptakes it via clathrin-coated vesicles
68
what is the role of HDL?
to recycle the lipids (cholesterol) back to the liver, where it can be used to make bile salts
69
how are HDL particles made?
- excess cholesterol is engulfed by macrophages
- ABCA1 forms pre-HDL, which is wrapped by ApoA-1, by flipping the cholesterol that is in inner layer of membrane to the outer (so acts as a transporter)
- LCAT esterifies cholesterol (makes cholesterol esters), which creates a spherical HDL due to change in hydrophobicity (went from amphiphilic to hydrophobic)
- maturation: CETP allows for the exchange of TGs and CEs between HDL and VLDL. they go with their concentration gradients, so TGs go inside HDL and CEs go inside VLDL
- mature HDL can now bind ApoA-1 receptor on liver, where it unloads the TGs and CEs
70
How is cholesterol synthesized? How much energy is required?
synthesized by mevalonate pathway:
- acetyl-CoA converted to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by ketogenesis
- HMG-CoA reductase converts HMG-CoA to mevalonate (requires NADPH)
- mevalonate eventually converted to a lipid anchor intermediate (Farnesyl pyrophosphate) -- requires a lot of energy (ATP)
- converted to squalene
- squalene converted to cholesterol
36 ATP and 16 NADPH/cholesterol
71
how is cholesterol synthesis regulated?
1. energy state:
- when in low energy state (high AMP/ATP), HMG-CoA reductase is shut of by phosphorylation -- when low energy, not enough energy to spare to make cholesterol
2. through gene regulation:
- SREBP is transcription factor for HMG-CoA reductase and LDL-R
- when low cholesterol: SREBP transported to Golgi, where can cleave transcription factors, which causes the induction of transcription
- when high cholesterol: SREBP associated with cholesterol, so doesn't go in Golgi
72
what do statins do?
they are HMG-CoA reductase inhibitors so decrease cholesterol synthesis
73
what are uses of cholesterol in the body?
1. storage as cholesterol esters
2. bile salts
3. hormones
4. vitamin D
74
What happens after a meal (intake of glucose and TGs) at rest in the following: pancreas, liver, muscle, brain, heart, adipose tissue.
pancreas: glucose taken up, causes release of insulin
liver: glucose
1. glycogen synthesis
2. FA synthesis
3. TG synthesis
4. storage in lipid droplets and/or VLDL secretion
liver: lipids
1. TG synthesis
2. storage in lipid droplets and/or VLDL secretion
muscle: glucose
1. glycogen synthesis
2. FA synthesis
3. TG synthesis
4. storage in lipid droplets and/or VLDL secretion
muscle: lipids
1. TG synthesis
2. storage in lipid droplets and/or VLDL secretion
brain: glucose intake and CAC cycle + OxPhos
Heart: glucose intake and CAC cycle + OxPhos
adipose tissue: glucose
1. FA synthesis
2. TG synthesis
3. storage in lipid droplets
adipose tissue: lipids
1. TG synthesis
2. storage in lipid droplets
75
What happens during exercise (glucose and lipid metabolism) in the following: liver, muscle, brain, heart, adipose tissue.
liver: glucose
1. glycogen breakdown (glucose released in circulation)
2. lactate intake (gluconeogenesis)
liver: lipids
1. lipolysis of TG in lipid droplets
2. FA export to blood
muscle: glucose taken in
1. CAC + OxPhos
2. glycogen breakdown
3. lactate formation, released in blood
muscle: lipids taken in
1. lipolysis of TG in lipid droplets
2. beta-oxidation of FA: used in CAC + OxPhos
brain: glucose intake and used for CAC + OxPhos
heart: glucose intake and used for CAC + OxPhos
Adipose: glucose: nothing
Adipose: lipids
1. lipolysis of TG in lipid droplets
2. FA export to blood
76
What happens during prolonged exercise or starvation (glucose and lipid metabolism) in the following: pancreas, liver, muscle, brain, heart, adipose tissue.
pancreas: glucagon produced
liver: glucose (exported to blood)
1. gluconeogenesis
liver: lipid
1. lipolysis of TG in lipid droplets
2. FA export to blood
3. ketogenesis (ketone bodies exported to blood)
muscle: glucose -- nothing
muscle: lipid (intake)
1. lipolysis of TG in lipid droplets
2. beta-oxidation of FA: used in CAC + OxPhos
brain: glucose and ketone bodies intake used for CAC + OxPhos
heart: glucose and ketone bodies intake used for CAC + OxPhos
adipose tissue: lipids
1. lipolysis of TG in lipid droplets
2. FA export to blood
