Lipid Metabolism Flashcards
How are lipids transported?
by lipoproteins (water soluble)
What is the origin of lipids?
-Exogenous (dietary sources)
-Endogenous (synthesized in the liver)
Definition of lipids?
a biological substance that is insoluble in water, but soluble in
organic solvents such as alcohol, chloroform, ether and acetone.
** some of phospholipids are not soluble in acetone & some have a limited
solubility in H2O
______ is important for reducing in lipid synthesis.
NADPH
What is the primary source of fuel for the body?
lipids
-50% of daily calories
What is the structural functions of lipids?
Components of cell membranes & other cell structures,
giving the cell membrane stability (& rigidity) and allowing
for transmembrane transport of important molecules
What is the hormonal function of lipids?
steroid hormones
Lipids functions for heat retention (brown fat) and ________ conduction (Myeline sheath)
nerve
*Energy can be generated from what major lipid?
(Free) fatty acids
What are the major lipids?
-(Free) Fatty Acids
* Phospholipids
* Cholesterol (Free & Esterified)
* Triglycerides
* Glycolipids
* Prostaglandins
- Consist of glycerol esters combined with free fatty acids
- Constitute majority of Neutral Fat (95% of tissue storage fat)
Triglycerides***
What is esterified cholesterol?
One fatty acid and one cholesterol (becomes hydrophobic)
What is like a hormone but not released into circulation, works locally?
Prostaglandins
What are triglycerides composed of?
3 fatty acids
How much of fatty acids are free?
Only a small percentage
Most are part of triglycerides
___________ supply almost half the calories burned for energy.
Fatty acids
What does saturated fatty acids depend on?
no double bonds
· Mono-Unsaturated, one double bond,
· PolyUnsaturated, 2 or more double bonds
Short chain FA are ______ carbon atoms.
4-6
Medium-chain FA are _____ carbon atoms.
8-12
Long-chain FA are ______ carbon atoms.
greater than 12
-needs special carriers (other than albumin)
Which is flexile, trans or cis form of fatty acids?
cis
Essential component of “Cell Membranes”
Phospholipids
Act as detergents in clearing other fats out of the body
AMPHIPHILIC STRUCTURE ENABLES BOTH FUNCTIONS
Phospholipids
Phospholipids serve as constituents of cell membranes and outer shells of ____________ molecules
lipoprotein
***Important phospholipids include:
✓ Lecithin (phosphatidyl choline) P choline
✓ Cephalins P ethanolamine, inositol, serine
✓ Spingomyelin (Spingolipid)
Spingomyelin (Spingolipid) have a _______ backbone.
Sphingosine
***Phospholipids are synthesized by…
the liver & intestinal epithelium
Lung surfactants are a mixture of _________ that decrease the fluid tension of the alveoli (preventing them from collapse)
lipoproteins
What causes Respiratory Distress Syndrome?
When premature infants do not secrete adequate amounts of lung surfactant thereby making lung expansion difficult
What phospholipids are examined to determine fetal lung maturity?
Amniotic fluid phospholipids
L/S (Lecithin: Sphingomyelin) ratios greater than 2 —-> decreased risk
L/S ratio alone is not a good predictor in…
diabetic, hypertensive and intrauterine growth retardation
***Lung maturity also correlates with the presence of….
Phosphotidyl glycerol
Surfactant containing PG (>2.1 mg/L) —> increase surfactant stability**
Synthesized endogenously from acetyl-CoA
cholesterol
- Unsaturated steroid alcohol
- High molecular weight—
4 perhydrocyclophenanthrone rings with side chain
Cholesterol
What enzyme do most cholesterol drugs work on?
HMG-CoA Reductase
(rate limiting enzyme)
-if this works endogenous cholesterol synthesis goes down. Therefore decreasing cholesterol.
What is found almost exclusively in animals?
cholesterol
***Important functions of cholesterol include:
- Manufacture and repair of cell membranes
- Synthesis of **bile acids
- Synthesis of Vitamin D
- Precursor of five major classes of Steroid Hormones
Precursor of five major classes of Steroid Hormones?
1) Progestins
2) Glucocorticoids
3) Mineralocorticoids
4) Androgen
5) Estrogen
The only fat that cannot be stored in the body
cholesterol *****
-excess gets made to bile acids and goes to intestines
What effect does aldosterone have on Mg, H, K and Na?
excretion of Mg, H, and K
reabsorption of Na
How is mean arterial pressure calculated?
MAP = CO x PR
How does the body obtain cholesterol?
Cholesterol in blood may be absorbed through diet, or endogenously synthesized in the liver
How is cholesterol excreted?
via bile salts into the intestinal tract***
-cannot be stored
About ____% of total body cholesterol is in stationary tissue (skin and muscle)
70
Only about ____% of total body cholesterol is mobile in the plasma.
30
- 1/3 free; 2/3 esterified with FA
How does HDL cholesterol get cleared?
HDL protien –> enzymes (LCAT and ACAT) —> ester —> free cholesterol —> to be cleared via liver –> bile salts –> intestinal tract
What does LCAT stand for?
Lecithin Cholesterol acyltransferase***
-Bound to Lipoprotein (HDL)
- Transfer FA from C2 of phpsphatidylcholin to cholesterol
Lecithin Cholesterol acyltransferase
What does ACAT stand for?
Acyl-CoA:Cholesterol acyltransferase***
Acyl-CoA + Cholesterol <——-> CoA + Cholesterol ester
How is cholesterol esterified?
- Lecithin cholesterol acyltransferase (LCAT)
- Acyl-CoA:Cholesterol acyltransferase (ACAT)
-Esterification of cholesterol by LCAT: _______
-Hydrolysis of cholesterol: ______
plasma
liver
What do TG consist of?
glycerol esters combined with three FAs
-constitutes majority of “neutral fats”
________ from adipose tissue and are the main storage from of fats.
TGs
How is fat used for energy during fasting or between meals?
Stored TGs can be catabolized into FFA
Plasma TG are derived from the…
intestine and liver
-intestinal TG is absorbed from dietary fat
What is the main source of plasma TG?
liver manufacture
What is the difference between vegetable TG and meat TG
veg-more unsaturated FA
meat- more sat FA
sugar-containing lipids
Glycolipids
(cerebroside: ceramide with a sugar at the 1-OH moiety).
What are two groups of glycolipids?
✓ Gangliosides—major membrane lipids of CNS
✓ Membrane glycosphingolipids—important for cell recognition
and blood typing
-Long-chain polyunsaturated FA (eicosanoids) with C20, including a
cyclopentane ring
* Synthesized in many tissues from arachidonic acid & other
polyunsaturated fatty acids
prostaglandins
What are the major classes of prostaglandins?
PGA –> PGI with subscripts indicating number of C=C double bonds PGA2
Prostaglandins and related compounds (thromboxanes, leukotrienes) are potent, and can alter the function of
both synthesizing and adjoining cells (very strong but short half life, regulator functions)
Chemical cell communication
Function like Hormone, but not hormone
Not stored , but synthesized as needed (short half-life)
prostaglandins
What are the three phases of lipid transport though the body?
-Digestive phase (intra luminal phase)
- Absorptive phase (cellular phase)
- Transport phase
Why must fats be “processed” for absorption?
fats are insoluble
Most fats are first emulsified by the action of ________.
bile salts
-then get acted upon by pancreatic enzymes, lipase, cholesterol esterase
How are cholesterol esters converted to free cholesterol & free fatty acids?
lipase, cholesterol esterase
Digestive phase:
Phospholipids are converted into…
other derivatives (lyso-derivatives)
[(phospho)lipase]
Digestive phase:
The micelles are complexes of…
MG, DG,, FFA, free cholesterol, phospholipids and bile acids.
What are the steps of the absorptive phase?
-Micelles come in contact with mucosal cells of the intestine
* MG & FA enter the ER of the mucosal cell, presumably by
diffusion
* Smaller FFA (<10 C) pass directly into portal circulation & attach to albumin
* In the intestinal cells, FFAs are re-esterified to form TG & CE (reassembled)
* Lipids are then packaged into chylomicrons for transport in the circulation
2% of Lipoproteins that shows dietary intake of TG
chylomicrons
What is the major protein in chylomicrons?
APO B-48
- large water soluble lipid-protein complexes of
phospholipid, TG, & cholesterol surrounded by a protein shell
***TG RICH
Chylomicrons
transport phase:
Mucosal cells release __________ into abdominal lymphatics
chylomicrons
(several hrs after meal, reverse pinocytosis)
-Chylomicrons enter the systemic circulation
-Carried via bloodstream to the liver & other tissue for use/metabolism
How long should someone fast when getting endogenous TG tested for?
10-14
Where do chylomicrons get transported to?
to all tissues (including adipose tissues, the principle site of uptake)
Transport phase:
TG are off-loaded & catabolized at extra-hepatic sites under influence of…
TG (lipoprotein) lipase (LPL)
TG-derived FFA may be stored or used for energy
- A TG remnant remains (a TG- poor, cholesterol-rich, highly atherogenic lipoprotein); removed by liver (as TG offloads, ration changes)
What is lipid used for?
- Metabolic fuel
- Synthesis into other material
- Complexed into specific lipoprotein carriers by the liver for transport to other parts of the body for use
How is lipid stored? ***
-Excess TG stored in adipose tissue
-Excess cholesterol excreted as bile salt
How is lipid synthesis regulated?
by feedback regulation by free cholesterol —-»»> HMG-CoA reductase
Lipids synthesized in liver, intestines, and other tissues
* Primary site of endogenous lipid production is the _______.
liver
Liver also produces apolipoproteins, which
are then packaged with newly formed TG,
phospholipids, & cholesterol to form the _____
VLDL
What carries endogenous TG?
What carries exogenous TG?
VLDL
chylomicron
Chain growth during FA synthesis takes place via successive additions of two carbon units (carboxylation), derived from “__________” —> Allow four carbon intermediates (third carbon is lost as CO2 during each cycle
malonyl CoA
***What is the key rate limiting step of fatty acid synthesis?
Formation of Malonyl-CoA from acetyl Co-A
***What is the rate limiting enzyme in fatty acid synthesis?
Acetyl CoA Carboxylase!
What increases Acetyl CoA Carboxylase? and what inhibits?
citrate
long chain Acyl CoA
B/C the bulk of acetyl CoA is formed in the mitochondrion, it has to
be transported to the cytosol in the form of _______ in order to become
a building block of fatty acid biosynthesis.
citrate
8 acetyl CoA molecules are used for the synthesis of one molecule of palmitate. This process also yield 8 NADPHs via the ____ enzyme reaction
malic
a total of 14 molecules of NADPH are needed for the synthesis of one molecule of palmitate.
* The additional NADPH are derived from…
the Pentose-Phosphate pathway
What does the reaction catalyzed by fatty acid synthase produce?
palmitate
What is not the rate limiting enzyme for FA synthesis?
Fatty acyl-CoA synthase (long term regulation?)
Fatty acyl-CoA
synthase and acetyl CoA carboxylase:
What all enhances enzyme synth?
-High carbohydrate diet
-Fat free (low fat) diet
Fatty acyl-CoA
synthase and acetyl CoA carboxylase:
What all decreases enzyme synth?
-High fat diet
-fasting
-glucagon
acetyl CoA carboxylase:
What agents cause allosteric activation? Enhancement?
citrate
insulin, dephosphorylation
acetyl CoA carboxylase:
What agents inhibit?
long chain acyl CoAs (allosteric inhibition)
glucagon, Phosphorylation (cAMP)
What is one of the most commonly occurring fatty acids?***
Palmitic acid
What is linked to ATP production?
-NADH + H+
-FADH2?
How do long chain fatty acids get into the mitochondria?***
Carnitine Acyltransferase
How are FAs of different chain sizes transported into membrane?
-short chain (2-4): free diffusion
-Medium (4-12): diffusion
-long chain (12-20): carnitine cycle
-very long chain (>20): unknown
What chain size of FAs can diffuse inside the mitochondria?
short and medium
When does beta oxidation take place?
-even number of carbons and it is saturated
NADH and FADH2 is produced from _________ and the TCA cycle.
oxidation
In Beta oxidation, what does the delta symbol mean?
the location of the double bond
beta oxidation:
What is detached in each cycle?
Acetyl-CoA
What does alternative FA oxidation pathway do?
moves the FA to trans position
a double bond on beta prevents oxidation, isomerase overcomes this by moving to trans to do beta oxidation
) Oxidation of unsaturated FA require additional enzymes and results in…
lower energy yield (2 ATP less/double bond)
-Each double bond is not
able to generate FADH2
rare reaction that moves one carbon out
alpha-oxidation
Oxidation of phytanic acid requires
alpha-oxidation
mitochondrial α-hydroxylase
a deficiency of mitochondrial alpha-hydroxylase
Refsum’s disease
-Autosomal recessive neurological disease
How are odd numbers of carbon fatty acids oxidized?
carbon gets added to the last metabolite
What sample type is used for measuring lipoproteins?
serum or whole blood
The liver only makes ________ , it becomes smaller after TG offloading to become LDL.
VLDL
____________ are the structural elements in the amphipathic shell of
lipoprotein particles
Apolipoproteins
-Apolipoproteins are complexed with lipids to form lipoproteins, which are
then soluble
What are the functions of apolipoproteins?***
-structural integrity of the complex
-solubility of the complex
-activate important enzymes in the lipoprotein metabolic pathways
*Facilitate the uptake of lipoprotein into cells through their recognition by
specific cell surface receptors
Different Apos require their __________ receptors
specific
Major apo of HDL; structural protein, activates LCAT; ligand for HDL binding
Apo A-I *
Structural protein in HDL; activates LCAT; enhances hepatic TG lipase activity
APO A-II*
Large major structural protein in VLDL & LDL; two forms
Apo B*
What are the two Apo B forms?*
✓ Apo B-100 synthesized in liver—found on VLDL, IDL, LDL
✓ Apo B-48 in the intestine—Found on chylomicrons
Binds to LDL receptor & (chylomicron) remnant receptor; several isoforms
Apo E***
What is included in Apo E
LDL, VLDL, & apo E-HDL*
iso-forms —> E2, E4, E3 (E2 worst for cholesterol and E3 being the best, know the order)
Structural protein for Lp(a); highly glycosylated apo; may inhibit plasminogen binding
Apo (a)
*Exogenous hyperlipemia:
elevated lipoprotein:
elevated lipid class:
chylomicron
triglycerides
*hypercholesterolemia:
elevated lipoprotein:
elevated lipid class:
LDL
cholesterol
*Combined hyperlipidemia:
elevated lipoprotein:
elevated lipid class:
LDL, VLDL
cholesterol, triglycerides
*Remnant hyperlipidemia:
elevated lipoprotein:
elevated lipid class:
beta-VLDL
triglycerides, cholesterol
*Endogenous hyperlipemia:
elevated lipoprotein:
elevated lipid class:
VLDL
triglycerides
*Mixed hyperlipemia:
elevated lipoprotein:
elevated lipid class:
VLDL, chylomicrons
Triglycerides, cholesterol
Ultracentrifugation results in separation based on _______ (VLDL, LDL,
HDL, etc.)
density
Electrophoresis is typically performed on…
agarose or cellulose
-Barbital buffer
*Stain with fat stain
Where do proteins stop on electrophoresis?
isoelectric point based on the proteins unique negative charge
Where will chylomicrons be seen on electrophoresis?
at the aspiration band (where it is loaded?)
mostly TG; very little protein; no electrophoretic
mobility; may not be present*
On electrophoresis, what side do the proteins move towards?
the positive end (proteins are negative)
-Results in band at point of application (sometimes), a beta band, a pre-beta band and an alpha band
Alpha band…
-fastest-mostly HDL *
Pre-beta band…
mostly TG, VLDL*
Beta band…
largest percentage of lipoproteins; mostly cholesterol, mostly LDL*
What is the order of lipoprotein separations by ultracentrifugation?
-Chylomicrons
* VLDL-Very Low Density Lipoproteins
* IDL-Intermediate Density Lipoproteins
* LDL-Low Density Lipoproteins
* HDL-High Density Lipoproteins
What is important for reverse cholesterol transport pathway?
HDL
-Densities of lipoproteins from ultracentrifugation of the serum
-Density unit is expressed as a Sf
Flotation units: Svedberg units?
Low density =_________ Sf units = float (lighter, more lipid)
High density = ________ Sf units = sink (heavier, more protein)
higher, low
What are the Lipoprotein Transport Pathways?
-exogenous pathway
-endogenous pathway
-reverse cholesterol pathway
Lipoprotein Transport Pathway:
transports dietary lipids via chylomicrons from the small intestine to the liver
Exogenous pathway
Lipoprotein Transport Pathway:
transports hepatic lipids via VLDL and LDL to the peripheral tissues
Endogenous pathway
Lipoprotein Transport Pathway:
transports cholesterol via HDL from peripheral tissues back to the liver
for excretion or reuse
Reverse cholesterol pathway
***What are the reverse cholesterol pathway steps?
- HDL (empty) produced in mainly the liver
- In the intestine, HDL binds free cholesterol from peripheral cells (macrophages)
- Cholesterol esterified by LCAT
- Cholesterol ester delivered to liver (for eventual excretion), several mechanisms
Step #4 of reverse cholesterol pathway, what are the several mechanisms that cholesterol ester delivered to liver?
✓ Direct uptake of HDL by liver via apo A
✓ Apo E-containing HDL binds LDL receptor or remnant receptor
✓ HDL exchanges cholesteryl ester to VLDL/LDL for TG
-CETP: cholesteryl ester transfer protein
HDL assembly is from __________ and ____________ sources.
cellular, intravascular
HDL from largest to smallest
2B, 2A, 3A, 3B, A-1
What is the importance of lipoprotein receptors?***
-Necessary for delivering lipoproteins to cells
-Necessary for efficient removal of potentially atherogenic
lipoproteins from the blood and peripheral tissues
Lipoprotein Receptors:
APO B-100 and APO E
▪ Cell binding
▪ Uptake and degradation of LDL
▪ Synthesis inhibited by high cholesterol level
▪ Defective receptors stimulates intracellular cholesterol synthesis
LDL Receptors
Familial hypercholesterolemia :
_____ % of LDL receptor defective
50
Lipoprotein Receptors:
-APO E
-Clearance of chylomicron and β-VLDL remnants from blood circulation
Remnant Receptors
Lipoprotein Receptors:
Surface of macrophage and muscle cells
▪ Mediate removal of modified LDL from blood circulation
▪ Macrophage with high cholesterol accumulation: Foam cells
Scavenger Receptors
Understand that excess citrate goes to _____________ synthesis.
fatty acid
What is the #1 cause for disability and #4 for death?
stroke
-CV disease is the leading cause of death in western
population
* Lipids deposit in vessels over time cause an
occlusion
* An increase in fats from either dietary intake or an
increase in endogenous production may result in
arterial plaque formation
What is the process that leads to occlusion?
Macrophage –> Foam Cells —> Fatty Streaks (previously damaged areas) –> Future injury —> More damage —>Plague formation—> Narrow vessel lumen —> Occlusion
What is in a lipid profile?
(1)Total and HDL cholesterol, with measured or calculated LDL cholesterol; (2)
Triglyceride determination; (3) lipoprotein electrophoresis
What is the relationship between HDL cholesterol and coronary risk?
inverse relationship
How do you calculate LDL/HDL Cholesterol Risk Ratio?***
✓ VLDL= TG/5
✓ LDL = total cholesterol-VLDL-HDL
LDL/HDL***
When can the LDL/HDL risk ratio not be used? ***
-chylomicrons are present
-serum triglyceride is greater than 400 mg/dl
LDL/HDL Cholesterol Risk Ratio for MALES:***
One-half average:
average:
twice average:
three times average:
One-half average: 1.00
average: 3.55
twice average: 6.25
three times average: 7.99
LDL/HDL Cholesterol Risk Ratio for FEMALES:***
One-half average:
average:
twice average:
three times average:
One-half average: 1.47
average: 3.22
twice average: 5.03
three times average: 6.14
Cephalins and lechithin have what backbone
Glycerol
CAD or CHD
Plaque formation in the heart is coronary heart disease (CHD) or
coronary artery disease (CAD)
PVD
Plaque formation in the arms and legs is peripheral vascular
disease (PVD)
CVD
Plaque formation in the brain causes cerebrovascular disease
(CVD)
