Lipid Metabolism

Lecture 20 & 21
I. Lipids are chemically diverse
Insoluble to H2Owhich contributes to the complexity in digestion, transport, & metabolism.
But, Highly soluble in non-polar solvents (chloroform/hydrocarbons/alcohols)

B. Major Categories
Triacylglycerol (TG)
Fatty Acids (FA)
Phospholipids (PL)polar/more amphipathic lipids
Glycolipids (GL)polar/more amphipathic lipids
Spingolipids (SL)polar/more amphipathic lipids
Steroids & Vitamins A, D, E, K

1) Neutral Lipids: non-polar esters of fatty acids w/ alcohols, glycerol, cholesterol
TG: 3 fatty acids each in an ester linkage w/ 1 molecule of glycerolform oily droplets in cytosol; source
of stored energy.
Most Natural Fats are mixtures of:
simple (contain same FA in all 3 positions) &
mixed (contain 2 or more diff FA) triacylglycerols.
Natural Oil: (olive oil, corn oil) mainly TGs w/ unsaturated FAs & therefore are liquids @ room temp!
Solid Fats: (butter, beef fat)saturated FAs raising the Melting Temp
Biological Waxes: esters of long-chain FAs w/ long chain alchols. Very high melting points, energy stores
& water-impermeable coatings. BEESWAX

Saturated vs Unsaturated FAs
Double bond introduces a kink in the tail & reduces it compactionthese are liquid @ room temp
Some essential fatty acidsthat can not be synthesized in our bodies (no desaturases), such as polyunsaturated fish
oils (Omega 3). (other fish oils are linoleic acid/arachidonic acid/Eicosapentanoic acid-EHA/Docosahexanoic acid-
DHA): There is growing medical literature about cardiology benefits & the molecular bases of these fish oils, they:
1) Inhibit TG synthesis
2) Enhance Lipoprotein Lipase Activity
3) Stimulate FA oxidation

Trans FAT
(Think Crisco)vegetable oil that has been partially hydrogenated w/ trans, not cis bonds make it stay solid @ room
temp.
Banned in restaurants in NYbased on a Havard Univ. Nurses Health Studywomen who at the most
trans FAs had a 53% increased risk of coronary heart disease compared to those who ate the least
4-6g/day is badtrans fat projected to deaths of 30,000 yr in US. Also contributes to Type II diabetes

2) Polar Lipids: contains a polar head group such as phosphate, sulfate, or carb. Amphipathic. Important
components of membranes

C. Biological Roles
1). Energy source: 9 Cal/g vs. 4 Cal/g (carbs). Efficiently stored in an anhydrous state (70 kg individual 85% stored
energy=fat)
Adipocytes-Fat Cells:
a) Can expand to accommodate increased lipid accumulation
b) have longevity
c) contain TG yielding (9 Cal/g)
d) fat is stored anhydrous
What are lipids good for?
2) Structure: major framework of membranes
3) Communication: steroid hormones (derived from cholesterol); PL, Vit D, prostaglandins & other factors derived
from arachchidonic acid; signal transduction.
4) Enzyme Co-factors: Vit K & other fat-soluble vitamins
5) Vision: Vit A
6) Digestion: Bile salts are derived from cholesterol; important in emulsification
7) Anti-oxidant: Vit E

II. Lipid Digestion
Highly efficient: avg adult intakes 60-160g fat/day (90% as TGs)
5% returns to environment as fecal fat. 95% recycled
To digest & absorb dietary fat must overcome 2 problems:
a) lipds are not very soluble in aqueous solution
b) lipid hydrolysis products aggregate & form large complexes that make poor contact w/
cell surface
Strategy for success:
a) increase surface area of lipid droplets by emulsificationaided by detergent propertied of bile salts &
mechanical mixing due to peristalsis
b) solubilization of hydrolysis products w/ detergents
How are these actions are implemented by the body:
1). The polar lipid represents a FA or PL/GL where 1 end is charged or H2O-soluble. Non-polar lipid oil or
nonpolar phases representing TGs, do not have a polar group & are completely H2O-insoluble
2). When polar lipids are added to H@O @ very low concentrations they will be solublebut as concentration ,
it reaches a critical concentration to from micelleshighly organized structures w/polar groups oriented
outward & non-polar inward
3). Emulsions:
large lipid droplets that are seen when shaking oil & H2O.
In contrast to micelles, there is visible cloudiness in emulsions due to light scattering by the particles.
Polydispersed (diff sizes) & no organized structure
Unstable suspension & will re-separate into phases, but can be stabilized by polar lipids (emulsifying agents)

B) Emulsification of Dietary lipids in Small Intestine
Synthesis of Bile Acids (occurs in the liver)
Cholic acid synthesis is the rate Limiting step in bile acid production
3 OH groups all face upward above plane of ringthis imparts a hydrophilic face
The Hydrophobic methyl groups face below the plane of the rings= Amphipathic structure
Cholesterol 7--Hydroylase converts cholesterol to cholic acid: the enzyme is (-) by cholic acid & (+) by
cholesterol

B1) Role of Bile Acids (Bile Salts)
Bile Salts are formed from bile acids & are cholesterol derivative; only significant mechanism for cholesterol
excretion
Formed in the liver
Sterol ring structure + an attached glycine (glycocholic acid) or taurine (taurochenodeoxycholic acid)
These emulsifying agents:
Interact w/ both lipids & aqueous duodenal contents
Stabilize lipid particles as they become smallerprevents coalescing
Stored in gallbladder & secreted into duodenum
Are effective detergents due to amphipathic structure
Fully ionized @ physiological pHenables fat (TG) emulsification in small intestine, stabilize particles &
prevents coalescence.
Main function in digestion is to form micelles
Provide only significant mechanism for cholesterol secretion (as metabolic products of cholesterol)
Necessary for absorption of cholesterol & fat-soluble vitains (AEK)
C). Process of Lipid Digestion
Dietary TG, cholesteryl esters, & PLs are enzymatically degraded by pancreatic enzymes whose secretion
into small intestine is hormonally controlled
a) TG Degradation/Digestion:
Micelles composed of TG molecules are too large to be taken up efficiently by mucosal cells of the intestinal
villiacted upon by Pancreatic Lipase
Major enzyme for FAs @ the 1 & 3 carbons
Pefers long-chain FAs (>12 carbons)
Rxn @ H2O/lipid interface of emulsion droplets
Requires Colipase: protein produced in pancreas/stabilizes the entire complex of: bile salts-TG-PL
Digestion by pancreatic lipase yields a smaller micelle that can be absorbed by intestinal mucosa
Absorption of Lipids w/in a Micelle by Intestinal Mucosal Cells
1) Action of bile salts in emulsifying fats in the intestine:
The hydrophobic surfaces of the bile salt molecule associate w/ TG & form a mixed micelle, w/ the
polar surface of the bile salt facing outward
This allows association w/ Pancreatic Lipaseliberating free fatty acids in a much smaller micelle
which can be absorbed thru the intestinal mucosa
Free FAs, free cholesterol, & 2-mononacylglycerl are primary products of dietary lipid
degradation in the small intestinetogether w/ bile salts this emulsion forms mixed micellesthese
are soluble in aqueous environment of intestinal lumen.
The micelles approach the primary site of lipid absorption, the brush border membrane of the
intestinal mucosal cellsthere component lipids are absorbed
2) Assembly & Secretion of Chylomicrons from Intestinal Mucosal Cells from Intestinal Mucosal Cells
Requires resynthesis of TG, Fatty Acyl CoA, Cholesteryl Esters
Apolipoprotein B-48 increases the solubility of Chylomicrons
After release into the intestinal lacteals the chylomicrons travel in the lymphatic systemthoracic
ductleft subclavian veinbloodstreamtissues
Glycerol & short chain FAs pass thru intestinal cell w/o modification via passive diffusion
Unlike CHO, no transporter proteins for entry to cells
GlycerolliverGlycerol 3-PhosphateDHAPGlycolysis or Gluconeogenesis
FA < 12 carbons in length: blood other tissues oxidation

b) Cholesteryl Ester Degradation
Cholesteryl esters are hydrolyzed by Cholesteryl Ester Hydrolase (Cholesterylesterase)producing
cholesterol + free fatty acid
c) Phospholipid Degradation
Phospholipase A2
Proenzyme activated by trypsin
Hydrolyzes a FA from carbon #2 of PL leaving a lysophospholipid (i.e. lecithin becomes lysolecithin)
Lysophospholipids are good detergents & help solubilize lipids in the intestine
Remaining FA @ carbon #1 removed by Lysophospholipase leaving glycerolphosphoryl base
(glycerylphohphorylcholine) that is either excreted in the feces or further degraded & absorbed

Processing of Dietary Lipids (v-16)
1) Bile salts emulsify dietary fats in the small intestine, forming mixed micelles
2) Intestinal lipases degrade TGs/Cholesteryl esters/PLs into 2monoacyglycerol/FAs/Cholesterol
3) FAs & other breakdown products are taken up by the intestinal mucosa & converted into TGs
(Resynthesis occurs w/in intestinal epithelial cell)
4) TGs are incorporated w/ cholesterol & apolipoproteins, into Chylomicrons
5) Chylomicrons move thru the lymphatic system & bloodstream to tissues
6) Lipoprotein lipase, activated by ApoC-II in the capillary, releases FAs & glycerol
7) FAs enter cells / glycerol goes to liver
8) FAs are oxidized as fuel or reesterified for storage
Summary of Lipid Digestion
1) Pancreatic Lipase: w/ Colipase generates FAs2-monoacylgyceol & glycerol
2) w/ aid of Bile Salts: FAs & monoacylglycerols are solubilized & transported to surface of the enterocyte
where they are taken up
3) Glycerol & FAs < 12 carbons DO NOT require a micelle for absorption by the intestinal mucosa they
can pass thru the cell into the blood (portal vein) w/o modification (via diffusion)=important consideration in
dietary therapy for individuals w/ malabsorption of other lipids
4) 2-monoacylglycerol & FAs >12 carbons are resynthesized into TGs in the ER
5) TGs then form into large lipid globules in the ER=Nascent Chylomicrons. Several apolipoproteins (i.e.
A-1 & B) are essential for this process
6) Nascent Chylomicrons: are released by exocytosis into the lymph system.
7) Bile salts are not taken up via passive diffusion into enterocytes but continue down the small intestine to
the ileum where they are taken up & returned to liver via active transport
Some Clinical Correlates:
Steatorrhea: occurs when excess lipids are excreted into feces due to lipid malabsorption from impaired
lipolysis, micelle or chylomicron formation or transport
Orlistat: an anti-obesity drug that unhibits pancreatic/gastric lipases, resulting in ~30% blockage of
dietary fat from digestion & absorptionleading to a reduction in body wt for many patients
Olestra: artificial fat composed of sucrose polyester backbone w/ 6-8 FA side chainsit is neither degraded
by pancreatic/gastric lipases & passes thru the body undigested & unabsorbed in intestinal cells.
Side effects: flatulence, bloating, & diarrhea. Excess use in foods may interfere w/ absorption of fat soluble
vitamins (A, D, E, K)
III. Lipid Transport
A. Lipoproteins/Apolipoproteins
Plasma lipoprotein particles are complexes of lipids & specific proteins called Apolipoproteins
These particles are dynamic as they are in a constant state of synthesis, degradation, & removal from
the plasma.
Particles serve to:
a) keep lipid soluble during transport in the plasma
b) provide efficient means for delivering & targeting lipid to tissues
Classification:
Note: Lipoproteins can be separated by centrifugation (density) or electrophoretic mobility
5 Main Classes:
1. Chylomicrons: least densehighest % TG, lowest %protein
2. VLDL: denser than chylomicrons but lots TG
3. IDL (intermediate): denser than VLDL but 50% TGs
4. LDL: less TG, more protein, denser than IDLhighest content of cholesterol & its esters
5. HDL: lowest %TG, highest %protein
Apolipoproteins: proteins that bind to lipidplay a role in transporting lipoprotein particles from 1
tissue to another
Synthesized in liver &/or small intesting
Designated Apo-A thru Apo-E w/ various subclasses
Apo Functions:
Structural components of lipoprotein particles
Enzyme activationthey activate enzymes that will metabolize the lipid in a given particle
1. Apo A-I activates LCAT
2. Apo C-II activates Lipoprotein Lipasewhich degrades TGs
Cell Recognitionprovides recognition sites for cell surface
1. Apo A-I is a ligand for HDL receptor
2. Apo B-100 is a ligand for LDL receptors
3. Apo E is a ligand for LDL receptors & the chylomicron remnant receptor
Lipid Transfer
Lipoprotein-Apolipoprotien complexes are stabilized by hydrophobic forces, not covalent bonds
Lipoproteins: Size decreases: chylomicron > VLDL > LDL > HDL --- size density & lipid protein
1) Chylomicronreleased from small intestinehighest TGlargest sizelowest density
Carries dietary TG to peripheral tissues/liver
Nascent form has Apo A-I & B-48; B-48
Later gets Apo C-II & E from HDL
2) VLDLgets TG from livercarries endogenous TG to peripheral tissuesfollowing lipoprotein lipase
activity in peripheral tissue capillary walls
Contains Apo B-100 in nascent form
Acquires Apo C-II & E from HDL
3) LDLformed from VLDL after exchange of TG & PL for cholesterol esters obtained from HDL
Highest cholesterolsupply it to the peripheral tissues
4) HDLsmallest sized lipoprotein particleHighest (apo)protein content (~60%)
Certain proteins are integral to this particle, while others are free to transfer to other lipoproteins.
Acceptors of unesterified cholesterol
At least 2 types HDL2 & HDL3
Structure of Plasma Lipoprotein Particle
Phospholipids, cholesterol & Apoprotein on surface --- neutral lipids (TG, CE) in the interior

Important Apolipoproteins of Human Plasma Lipoproteins
Apolipo Lipoprotein Comments/Functions
Apo A-1 HDL
Chylomicrons
Activator of lecithin:cholesterol acyltransferase (LCAT/PCAT)
Ligand for HDL receptor
Apo B-
100
LDL
VLDL/IDL
Synthesized in liver
Ligand for LDL receptor
Apo B-48 Chylomicrons
Chylomicron Remnants
Synthesized in intestine
Ligand for Chylomicron Remnant
Apo C-II VLDL/HDL
Chylomicrons
Activator of Lipoprotein Lipase
Apo E VLDL
HDL
Chylomicrons
Chylomicron Remnants

Present in excess in the -VLDL of patients w/ Type III
hyperlipoproteinemia.
Sole Apoprotein found in HDL of diet-induced
hypercholesterolemic animals
Ligand for chylomicron remnant receptor - liver/LDL receptor

B. Metabolisim of Chylomicrons
1) Assembly: assembled in intestinal mucosal cells
Chylo carry dietary TG, cholesterol, & cholesteryl esters to peripheral tissues & liver
Apos are synthesized in the RER
Apo & lipids are assembled into chylo during transition from ER to Golgithen packaged into secretory
vesiclesare exocytosed from the cell into the lymphatic system

2) Modification of Nascent Chylomicron Particle Modification
Particle released by intestinal mucosal cell = Nascent chylomicron; contains Apo B-48
In plasma the nascent receives Apo E & Apo C-II from circulating HDL
Note:
a) Apo E + Apo B-48 are recognized by hepatic receptors
b) Apo C-II activates lipoprotein lipasewhich degrades TG present w/in chylomicron

3) Degradation of TG by Lipoprotein Lipase
Lipoprotein Lipase located on capillary walls on most tissuesfound mostly in capillaries of adipose
tissue, cardiac, & skeletal muscle. It is activated by Apo C-II on circulating lipoprotein particles &
hydrolyzes TG (yielding monoacylglycerol/glycerol/fatty acids)
Type I Hyperlipidemia: Deficiency in either the Lipase or Apo C-II results in accumulation of TG-rich
lipoproteins in plasma
4) Apo C-II returned to HDL
5) Formation of Chylomicron Remnants
As the chylomicron circulates, its TG is degraded by LL resulting in a in particle size & in density
due to fatty acid release
Apo C-II returned to HDLs
Remaining particle is referred to as chylomicron Remnant
Liver plasma membrane contains receptors that recognize Apo B-48 + Apo Ethe chylomicron
remnants bind & are taken into liver via endocytosis
Following fusion of endocytosed vesicle w/ lysosome, the particles contents are hydrolyzed to amino
acids, cholesterol, & FAs.

C. Metabolism of VLDL
VLDL are produced in the liver/consist mainly of TG/carry TG from liverto peripheral tissuesthen TG is
degraded by LL which is activated by Apo C-II
1) Release of VLDL
VLDLs are released from liver in nascent form/contain Apo B-100
They obtain Apo C-II & Apo E from circulating HDL
As w/ chylomicrons, Apo C-II activates LL
2) Modification of Circulating VLDL
VLDL structure is altered passing thru circulationTG is removed by LL causing VLDL to in size &
in density
Apo C-II & Apo E returned to HDL
Cholesteryl Esters transferred from HDL to VLDL in exchange rxn that concomitantly transfers either
TG or PL from VLDL to HDL
Cholesteryl Ester Transfer Protein catalyzes exchange
3) Production of LDL from VLDL in Plasma
Following these modificationsVLDL has been converted to LDLduring the transition, an
intermediate sized particle, IDL, is observed
IDLs are also taken by cells via endocytosis
4) Apos C & E returned to HDL
5) Binding of LDL to Specific Receptors
LDL binds via Apo B-100 & Apo E to receptors on both liver & extrahepatic tissues where they are
endocytosedtherefore, LDL delivers cholesterol to peripheral tissues or returns it to the liver

D. Comparison of Chylomicron vs. VLDL
Chylomicrons are larger & contain more TG than VLDL
Chylos are major carriers of dietary TG (exogenous)
VLDLs are major carriers of TG synthesized in liver (endogenous)
Maturation of both types of particles occurs by acquisition of Apo C-II & Apo E from HDL
Apo B is essential for formation of each type of particle: Apo B-48 (chylo) & Apo B-100 (VLDL)
Following lipolysis in tissues, the chylomicron remnant, having lost 90% TG is endocytosed (taken up
by liver cells)this is mediated by specific receptor for Apo B-48/Apo E.
Following lipolysis, VLDL becomes IDL & LDLthe cholesterol-rich LDL is taken up by extrahepatic
tissues (~50%) & liver (~50%)LDL uptake requires a receptor specific for Apo B-100/Apo E.
Both are metabolized by LL present in capillaries of extraheptic tissue
Apo C-II is required to activate lipase activity
Clinical Connection:
Abetalipoproteinemia (a HYPOlipidemia)Apo B is not made so neither chylomicrons nor VLDL are found in
serum. Lipid droplets accumulate in both liver & intestinal cells.




Hypolipidemias
Name Defect Remarks
Hypolipoproteinemias
Abetalipoproteinemia

(on BOARDS)
No chylomicrons, VLDL, or LDL are
formed due to defect in triacylglycerol
transfer protein (MTP)prevents the
loading of Apo B w/ lipid
Rare
Blood acylglycerols low
Intestine & liver accumulate acyglycerols
Familial Hypobetalipoproteinemia LDL concentration is 10-60% of norm Chylomicron formation still occursmost individuals
healthy & long-lived
Familial Alpha-lipoprotein Deficiency
Tangier Disease (Orange Tonsils)
Fish-eye Disease
Apo-A-I Deficiences
All have low or near absence of HDL No impairment of chylomicron or VLDL
formation.
No pre--lipoprotein but broad -band on
agarose electrophoresis; tendency toward
hypertriacylglycerolemia as a result of
absence of Apo C-IIwhich activates
lipoprotein lipase.
Low LDL levels.
Atherosclerosis in elderly

Hyperlipidemias
Diseasae Description Biochemical Finding
Type I
(on Boards)
Rare genetic disorders of Lipoprotein Lipase
Deficiency or Apo C-II deficiency
Cholesterol High
Chylomicrons High
TGs extremely elevated @ 1,000-10,000mg/dL
Slow Clearance of Chylo & VLDL
Treatment=reduce fat/CHO
Type IIa (most common) Common Familial Cholesterol & LDL High
TGs normal
Autosomal dominant inheritance
Defective LDL receptors
Atherosclerosis
CHD
Type IIb Classic Mixed (both LDL/VLDL High)
hyperlipidemia
Cholesterol & LDL/VLDL high
TGs < 1000
Autosomal dominant inheritance
Reduced LDL clearance
Type III Dysbetalipoproteinemia
(Deficiency ApoE)
Cholesterol high
IDL (a VLDL remnant)
Abnormal ApoE
TGs < 1000
Less Common Familial
Type IV (most common) Endogenous Hypertriglyceridemia:
Hyperprebetalipoproteinema
Cholesterol normal
VLDL high
Triglycerides < 1000
Common Familial
Associated w/ Coronary heart disease (CHD)
Type II Diabetes (glucose intolerance)
Obesity
Type V Hyperprebetalipoproteinemia w/
chylomicronemia
Cholesterol High
Chylomicrons & VLDL high
TG extremely elevated @ 1,000-10,000 mg/dL
Uncommon familial
Normal TG Values: Male = 35-135 mg/dl, Female = 40-170 mg/dl

E. Metabolism of HDLs
HDLs are synthesized in the liver & released into the blood via exocytosis
Functions of HDL:
1) As a Reservoir of Apolipoproteins:
Provide apolipoproteins necessary for other plasma lipoproteinsincluding Apo C-II & Apo E to
both Chylomicrons & VLDLs
HDLs recover most of these proteins before chylo remnants & LDLs are endocytosed
2) Uptake of Cholesterol:
Freshly secreted (nascent) HDL consists of: unesterified cholesterol, PL, & several Apos
HDL particles are excellent acceptors of unesterified cholesterol fromother circulatind
Lipoproteins & the cell membrane surface
Flattened disc become more spherical as they accumulate cholesterol
3) Esterification of Free Cholesterol:
After removing free (unesterified) cholesterol from extrahepatic tissues HDLs esterify it using the
plasma enzymePhosphatidylcholine Cholesterol AcylTransferase (PCAT) or (LCAT-lecithin)
The cholesteryl ester is very hydrophobic & is trapped in HDL; no longer transferred to a
membraneRemember: only mechanism for removing cholesteryl ester from HDL is VIA transfer
to VLDL via the CHOLESTERYL ESTER TRANSFER PROTEIN=CETPwhich transfers
cholesteryl esters to VLDL in exchange for TG or PL.
Following exchange, cholesteryl ester will remain in LDLs until they are endocytosed into a given
cell.
4) Fate of HDLs:
HDLs are taken up by the liver via Endocytosisthus they carry cholesteryl esters to the liver
HDL is then degraded & free cholesterol is releasedwhich can be:
-repackaged in lipoproteins
-converted into bile acids
-secreted into bile for ultimate removal from body

IV. Metabolism of TGs in Tissue
1) Fatty Acids are released in capillaries by LL are taken up by tissues & either metabolized to CO2 (muscle) or
resynthesized into TGs (adipocytes)
2) Mobilization of Stored Fat
Hormone-sensitive lipase initiates the hydrolysis of TGs to yields FAs (from either C-1 or C-3) &
glyceroladditional lipases then take over
FAs can either be exported to other tissues or can be metabolized to CO2
3) In adipose tissuethe lipase is activated by epinephrine, norepinephrine, & glucagon as follows:
These hormones bind to receptors on plasma membrane adenylate cyclase activity, cAMP,
Protein Kinase A activitythereby phosphorylating & activating lipase (like glycogen phosphorylase
activation by phosphorylation)
Insulin inhibits lipolysis by promoting lipase Dephosphorylation
Note: Acetyl CoA Carboxylasethe rate limiting enzyme in FA synthesis, is inhibited by hormone-
mediated phosphorylation
So, if cAMP-mediated cascade is activatedFA synthesis if turned OFF & TG degradation turned ON
4) Adipocytes cant metabolize released glycerol since they lack Glycerol Kinase. Glycerol is transported to the
liver where it is converted to DHALglycolysis
Most cells can oxidize free FAs to supply energy except they cannot be used by the brain as they are too
large to cross the blood brain barrier

Summary of Lipases
Enzyme Origin Site of Action Function Special Properties
Gastric Lipase Stomach Stomach Degrades dietary TGs containing short-
chain FAs
Acid-stable
Pancreatic Lipase Pancreas Small Intestine (lumen) Degrades dietary TGs (removes FAs
from Carbon 1 & 3, leaving 2-
monoacylglycerol)
Requires Pancreatic
Colipase for stabilization
Lipoprotein Lipase Extrahepatic
tissues
Surface of endothelial cells lining
capillaries
Degrades TGs circulating in chlomicrons
or VLDL releasing non-esterified FAs &
glycerol
Can be released into
plasma by Heparin
Activated by Apo C-II
Hormone-Sensitive
Lipase
Adipocytes Adipocytes (cytosol) Degradation of stored TGs Activated by cAMP-
dependent kinase
Gemfibrozil: a member of the bibrate lipid lowering drugs, activates lipoprotein lipase. VLDLs decrease as
do other TG-rich lipoproteins
Niacin: decreases cAMPso it inhibits hormone-sensitive lipase lowering serum VLDL, LDL, & TG. Also,
reduced HDL clearance (serum HDL increases). Treatment is cheap & effective but contraindications=
flushing, itchiness, dyspepsia (upset stomach).
V. Metabolism of Fatty Acids (FAs)
1) Activationupon entry into a tissue a FA must be activated before resynthesis into a TG or breakdown to
CO2
Acyl CoA Synthetase (aka fatty acid Thiokinase) catalyzes the rxn in the outer mito membrane
You pay to playactivation costs energetically ~2 ATP
2) Transport of Long Chain FAs (Acyl-CoAs) into Mito
<12 Carbon fatty acyl CoAs passively diffuse thru the mito inner membrane
>12 Carbon fatty acyl CoAs are specifically transported across the inner membrane
Basic strategyConvert acyl CoA to an acyl carnitine derivative, which is transportedthen regenerate
the acyl CoA w/in the mito matrix
Note:
Carnitine is a zwitterionic compound, formed from lysine, which acts as a shuttle to bring >12 carbon fatty
acids CoAs across the inner mito membrane where -oxidation can take place
Enzymes Carnitine Palmitoyl Transferase I, II (CPT I, II) aka Carnitine Acyltransferase I & II
CPT I is located on the outer mito membrane (OMM)= Rate limiting step (Malonyl CoA (-) CPT I)
CPT II is located on the inner mito membrane (IMM)
Clinical Connection:
CPT I Deficiency: results in intermittent ataxia, oculomotor palsy (CN III), hypotonia, mental confusion,
disturbance of consciousness
3) Regulation:
The principal point of regulation of FA oxidation is via inhibition of carnitine palmitoyl-transferase I
by Malonyl CoA
Important points:
a) Inhibition occurs @ the 1
st
committed step (as it often does) in the FA oxidation pathway
b) Reciprocal regulation of degradative & synthetic pathwaysthus, when FA synthesis occurs (producing
Malonyl CoA), FA oxidation is inhibited
4)Catabolism of Fatty Acyl CoAs in the mito Matrix- 4 Step Program
Degradation of FAs proceeds 2 carbons @ a time, starting from carboxyl end
Rxns occur in the mito matrixconsists of an Oxidation/Hydration/Another
Oxidation/Thiolysis (cleavage rxn involving CoA to produce a Fatty Acyl CoA 2 carbons shorter
than the original FA + a molecule of Acetyl CoA). The process repeats continuously
Oxidation rxn directly feeds reducing equivalents to respiratory chain to make ATP
The released Acetyl CoA enters the CAC which will yield additional ATP
5) Energy Yield of FA Oxidation
1 Cycle: NADH (2.5) + FADH2 (1.5) + Acetyl CoA (10) = 14 ATP generated per cycle
Example: Palmitate (16 Carbons)
7 cycles of oxidation (28) + 8 Acetyl CoA produced (80) Fatty Acid Activation (2) = 106 ATP
Initial activation step: breaking both phosphoanhydride bonds in ATP; energetically equivalent to 2 ATP
6) Oxidation of unsaturated FAs (~ FAs in human lipids)
For Mono Unsaturated FA
Cis is natural configuration
However, only the trans isomer is oxidized via -oxidation. Trans configuration is generated by
Enoyl CoA isomerase step which converts a cis double bonded carbon to trans double bonded
carbon
The pathway then proceeds as it does for saturated FAs
FA oxidation strategy:
-oxidation occurs until the double bond of unsaturated FA is near the carboxyl end of fatty acid acyl chain.

For Poly Unsaturated FA
2 accessory enzymes required: 2,4-dienoyl CoA reductase & cis--3 Enoyl isomeraseenables the
oxidation of poly-unsaturated FAs containing a cis double bound @ an even-numbered carbon atom


VI. Minor Pathways of FA Metabolism
1) Odd-Chain FAsrepeat 4 steps of -oxidation until last cleavage
Most naturally occurring lipids contain FA w/ an even number of carbonslipids of plants & certain marin
organisms have FA w/ an odd number of carbonds
Oxidation of odd num carbon FAs yields Acetyl CoA & Propionyl CoA (C3) in the final round
Propionyl CoA goes into the TCA (converted to glucose) after conversion to Succinyl CoA
2) Peroxisomal Fatty Acid -Oxidation
Where? Preliminary -oxidation occurs in Peroxisomes
What? Very long-chain FAs (>20 C); requires CoA; yields no energy in peroxisome (NO ATP), just HEAT
(thermogenesis)
Products? H2O2broken down by catalase to H2O/ O2/octanoyl CoA (8 C) that diffuses into cytosol & into
mito/NADH/Acetyl CoAthese products are broken down further in mito
So? This pathway can be substantial under conditions such as high fat dietleads to heat generation

Comparison of -oxidation in mito & peroxisomes
The peroxisomal system differs from mito system in 2 respects
1) In the 1
st
oxidative step electrons pass directly to O2 generating H2O2
2) NADH formed in the 2
nd
oxidative step cannot be reoxidized, so reducing equivalents are exported from the
peroxisome to the cytosol. Acetyl CoA produced in mito is further oxidized in the TCA

Clinical Connections:
Zellweger Syndrom: a peroxisomal disorder resulting in accumulation of very long chain fatty acids
(VLCFA)because the peroxisome is not properly formed. Clinical manifestations include congenital craniofacial
dysmorphism/psychomotor retardation/seizures. Death in the 1
st
year of Life
Adrenoleukodystrophy: rare metabolic disorderVLCFA accumulate in the brain (causing demyelination) & in
the adrenal cortex (causing degeneration) because of inability to transport VLCFA into peroxisomes. Clinical
manifestations include psychomotor retardation & seizures

3) -oxidation
Where? Occurs in the peroxisomes of mainly brain & other nervous tissues
What? Branched chain (methylated phytanate) FAs that are found in plants
intial oxidation occurs @ carbon 2 () instead of -carbon following its hydroxylation; carboxyl atom is
released as CO2.
The carbon contains a branched group & thus is not a substrate for the Acyl CoA Dehydrogenase
FA degraded 1 carbon @ a time yields NO energy, Does NOT require CoA; followed by -oxidation
Refsumss disease: a genetic defect due to lack of hydroxylating enzyme (motor & sensory neuropathy
Type IV)

4) -oxidation (most minor)
Alternative to -oxidation begins w/ oxidation of carbon most distant from the carbon =
The substrate is usually a medium-chain fatty acid
This pathway is generally not the major route for oxidative catabolism of FAs
Oxidation starts @ terminal methyl group which is oxidized to a carboxyl group
Where? Smooth ER (cytochrome P450 pathway)
What? C10-C14 FAs that are released from adipose tissue in ketosis
Yields NO energyproductos dicarboxylic acid

VII. Ketone Body Synthesis/Utilization
Ketone bodies refer to 3 compounds: 3-hydroxybutrate/Acetate/Acetone
these are produced by the liver & utilized by extraheptic tissues
produced in small amountsbut are greatly increased during fastin, in high fat diets, & diabetes
Acetyl CoA produced via FA oxidation can enter TCA only if sufficient OAA exists
When there is insufficient carb (fasting or diabetes) OAA is consumed to form glucose (via gluconeogenesis)
Note: OAAPEP is catalyzed by PEP-carboxykinase, present in liver, but absent in muscle & heart. Thus no
depletion of OAA in muscle & heart, so incoming Acetyl CoA is utilized
Depletion of TCA OAA in liver causes Acetyl CoA to be diverted to ketone body productionsso FA
oxidation continues when Acetyl CoA is not being oxidized by cycle
HMG CoA Synthase is the rate limiting Stepit is present in significant quantities only in liver
Clinical Connection:
Type I diabetes mellitus: caused by insulin deficiencyleads to diabetic ketoacidosis; a severely elevated
serum glucose level, ketone body synthesis, forming acetone (strange, fruity scent on the breath) due to
decarboxylation of acetoacetateacetone)

Utilization of Ketone Bodies by Peripheral Tissues
The liver lacks CoA Transferase (also called Thiophorase) & therefore cannot utilize Ketone Bodies as an energy
source for itself

VII. Sythesis of Fatty Acids Lipogenesis
Fat is synthesized from either carb or protein when caloric intake exceeds daily requirements
When well fed, ATP is abundant, Acetyl CoA is diverted to energy storage as FAs
Biosynthesis can not take place in mito
De novo FA synthesis occurs in the cytosol
Need to ship Acetyl CoA out but can not transport Acetyl CoA directly to cytosol
A. Citrate Acts as a Carrier of Acetyl CoA from the Mito Matrix to Cytosol
B. Fat synthesis Requires NADPH (reducing equivalents)
Malic enzyme provides ~50% of required NADPHremainder from Pentose Phosphate Pathwy
C. Forming Malonyl CoA = Committed Step in FA Synthesis
a) Carboxylation of Acetyl CoA to Malonyl CoA via Acetyl CoA Carboxylase = the 1
st
rate limiting &
committed step in FA synthesis. ACC contains biotin as a prosthetic group for carboxylation
Remember: synthesis produces Malonyl CoA which inhibits FA oxidation by inhibition of CPT
Ireciprocal regulation
I) Types of Regulation of ACC:
1) Allosteric: starts as an inactive dimer that is activated (+) by Citrate & inhibited (-) by long chain Fatty Acyl
CoA. When activated it is an active polymer that converts AC to MC
2) Hormonal: Insulin activates Protein Phosphatase which dephosphorylates ACC converting it to active form.
Glucagon/epinephrine activate cAMP-dependent Protein Kinase which phosphorylates/inactivating ACC.
So phosphorylation inactivates the enzymes (when blood glucose low, will breakdown fat, not synthesize it)

II) Acetyl CoA is Carboxylated in 2 Stages
1) Carboxybiotin intermediate formed @ expense of 1 ATP
Biotin-enzyme + ATP + HCO3- CO2 ~ biotin-enzyme + ADP + Pi
2) The activated CO2 group is then transferred to Acetyl CoA to form Malonyl CoA
CO2~biotin-enzyme + acetyl CoA Malonyl CoA + biotin-enzyme
Count carbons: 1C (CO2) + 2C (AC) 3C (MC)

III. Acetyl CoA Carboxylase from bacteria has 3 polypepide subunits. Animal cells, all 3 activities on
multifunctional Single polypeptide
1
st
Subunit: Biotin is attached to a protein called Biotin Carboxyl Carrier Protein (BCCP)
2
nd
Subunit: Biotin Carboxylase which catalyzes the carboxylation of this Biotin
3
rd
Subunit: Transcarboxylase catalyzes the transfer of the activated CO2 from carboxy biotin to Acetyl CoA

Acyl Carrier Protein (ACP)
All the intermediate FA oxidation (inside mito) are activated via their linkage to CoAa similar activation
occurs during FA synthesis in the cytoplasm
Activation involves the ACPa small cytoplasmic protein that contains a 4-phophopantetheine prosthetic
group derived from the vitamin pantothenic acid
Its SH group is the site of entry of the malonyl & acetyl groups during FA synthesis
There is also a cysteine residue in the protein; both sulfhydryl groups of the pantothenic acid & the proteins
can form thioester linkages w/ the acyl groupthese linkages function to activate these groups
ACP plays a similar role to that of CoA during FA oxidationwhich also uses a phosphopantothene group
The long flexible pantetheine arm of ACP can reach all the active sites in Fatty Acid Synthase
The elongation phase of FA synthesis starts w/ the formation of acetyl-ACP & malonyl-ACPthey are
linked via the sulfhydryl terminus of the ACP phosphopantetheine group
Note: FA having an odd number of C are synthesized starting w/ propionyl CoA

D. The rest of the Fatty Acid Synthesis Spiral
Sequence in the synthesis of FA in E. Coli: Condensation Malonyl CoA (3C)-CO2 = 2C
ReductionDehydrationReduction
Fatty Acid Synthase enzyme complex that catalyzes these rxns
In eukaryotes the enzyme is a dimer w/ each monomer having 7 diff enzymatic activities plus a domain
that covalently binds 4-phosphopantetheine.
In prokaryotes, the latter domain is a separate protein (ACP). To start the 2
nd
cycle, butyryl-ACP
condenses w/ malonyl-ACP to form hexaonyl-ACP, and so on & so on
Note: Malonyl-ACP feeds in @ each cycle
The same pattern continues until the product of the 7
th
cycle, palmitoyl-ACP undergoes hydrolysis to
yield palmitate & free ACPAcetyl ACP keeps feeding in after the initial Malonyl ACP

High Yield Summary: Diffs btw FA de novo Synthesis & FA Oxidation
Parameter Fatty Acid Oxidation Fatty Acid Synthesis
Intracellular Location Mito Cytoplasm
Carrier CoA ACP
Coenzymes for e- transfer FAD, NAD NADPH
Bicarb dependence No Yes
Energy State favoring the Process High ADP (Low Energy) High ATP
Citrate Activation No (but Malonyl CoA) Yes
Acyl CoA inhibition (long chain) No Yes
Highest Activity Fasting, Starvation Carbohydrate Fed
Hormonal State
Insulin/Glucagon Ratio
Low High
Carrier of Acyl/Acetyl Group Carnitine (cyto to mito) Palmitate (mito to cyto)
Product Acetyl CoA Palmitate
Repetitive Process Dehydrogenation (oxi)
Hydration
Dehydrogenation (oxi)
Thiolysis
Condensation
Reduction
Dehydration
Reduction

X. Summary of Fat Metabolism & Its Reduction
Important enzymes: citrate synthetase/ATP-citrate lyase/malic dehydrogenase/malic enzyme (generates NADPH for
fat synthesis)/pyruvate carboxylase/pyruvate dehydrogenase








Complex Lipids
Introductory Points:
Includes: Acylglycerols (major lipids in the body), Phosphoglycerides (glycerphospholipids), & Sphingolipids
I) Acylglycerols
TGs = major lipids in fat deposits & food
In adipose tissue TGs are stored in a highly reduced, nearly anhydrous stateserving as the major stored fuel
Mono-, di-, & triacylglycerols contain 1, 2, 3 molecules of FA esterified to a molecules of glycerol
FAs are esterified thru their carboxyl groupsresulting in loss of (-) charge & formation of a neutral fat
FAs must be activated by attachment to CoA before they can participate in TG biosynthesis
Biosynthesis of TGs
TGs are synthesized in liver & fat cells
2 major precursors are required: 1) L-glycerol 3-phosphate ; 2) Fatty Acyl CoAs
Sources of L-Glycerol 3-Phosphate
1) Reduction of DHAP by Glycerol Phosphate Dehydrogenaseoccurs in liver/adipose
2) From free glycerol (originated from TG degradation) via the action of Glycerol KinaseLiver only (a lot of it)

Note: Adipocytes take up glucose only in the presence of insulinso, when plasma glucose & insulin are low, adipocytes
limit ability to synthesize glycerol 3-phosphateso cannot produce TGs=Non-fed/starving State

Source of Fatty Acyl CoA: FA must be activated (attached to CoA) before participation in TG biosynthesis

Biosynthesis of TGs (Major Pathway)
Steps include:
1) Acylation of Free hydroxyl groups of Glycerol by 2 molecules fatyy acyl CoAto yield Lysophosphatidic Acid & then
Phosphatidic Acid. Rxns catalyzed by Glycerol Phosphate Acyltransferase
2) Phosphatidae Phosphatase hydrolyzes Phosphatidic Acid to form diacylglycerolwhich is a key molecule in
phospholipid biosynthesis
3) Diacylglycerol reacts w/ a 3
rd
molecule of fatty acyl CoA via action of Diacylglycerol Acyltransferase to yield a TG

II) Phospholipids (Glycerol-based)
A) Structures
The parent compound is L-glycerol 3-Phosphate
2 OH groups are esterified to fatty acids
The 3
rd
OH group is esterified to phosphoric acid
2 major classes:
1) those that have a glycerol backbone
2) those w/ a spingosine backbone
PL contain a polar head group + nonpolar hydrocarbon tails & so are called polar lipids=amphipathic
Polar head groups are contributed by: Amino Alcohols=ethanolamine/choline Amino Acid=serine6-carbon
Cyclic Sugar Alcohol=inositol
Most abundant PL in higher plants & animals include
Phosphatidylcholine (Lecithin) - neutral
Phosphatidylethanolamine (Cephalin) Neutral
Phosphatidylserine Net (-) charge
Phosphatidylinositol Net (-) charge
Clinical Connection:
Respiratory Distress Syndrome (RDS): occurs in premature infants due to a deficiency of surfactant in lungsleading
to decrease in lung complianse. Dipalmitoyl Phosphatidylcholine (DPPC aka Lecithin) is the primary PL in surfactant
which lowers surface tension @ the alveolar air-fluid interface. Surfactant is normally produced @ gestation wk 30.

Variations in size, shape, polarity & charge of polar head groups play an important role in membrane structure.
Note: if FA @ either carbon 1 or 2 of Phospholglyceride is removed, a Lysophosphoglyceride results

Phospholipases Hydrolyze Phospholipids2 roles:
1) digestive enzymes present in intestinal juices, bacterial secretions, & venoms
2) generate highly active signal molecules or their immediate precursors
Phospholipase A2:
Present in many mammalian tissues & pancreatic juice. Also in snake/bee venom
Acting on P-inositolreleases arachidonic acid (precursor of prostaglandins)
Pancreatic secretions are especially rich in its proenzymewhich is activated by trypsin & requires bile salts for
activity
Is inhibited by Glucocorticoids (cortisol)
Phospholipase A1
Present in many mammalian tissues
Phospholipase D
Plant tissues
Phospholipase C
Liver Lysosomes & the -toxin of clostridia & other bacilli
Activated by PIP2 system plays a role in producing 2
nd
messengers

B) Biosynthesis (Glycerol-containing PLs)
PL are synthesized from PA + an alcohol in the SERthen transported to Golgi Apparatusthen to
intracellular membranes or Plasma Membrane. Can also be secreted by exocytosis
1
st
step is shared w/ TG biosynthetic pathyway: G3pPADiacylglycerolTG
1
st
route= 2 fatty acyl groups are esterified to C1 & C2 of L-glycerol 3-phosphate to form phosphatidic acid
2
nd
route to PA= phosphorylation of diacylglycerol by specific kinasethen PL synthesized by PA + alcohol
PL head group is attached to diacylglycerol by a Phosphodiester bond formed when phosphoric acid
condenses w/ 2 alcohols
1of the hydroxyl groups must first be activated by attachment of nucleotide, Cytidine Diphosphate (CDP).
CMP is then displaced
Strategy 1: CDP attached to Diacylglycerolactivating it
Strategy 2: CDP attached to OH moiety on polar head group
Phosphatidate is precursor of both Phosphoglycerides & TG
PG: Phosphatidyl-glycerol is precursor for Cardiolipin
PI: is formed from free myo-inositol & CDP-diacylglycerol & it serves as reservoir of arachidonic acid in membranes
(it contains arachidonic acid on C-2 of glycerol)
PC & PE: most abundant PLs. Primary route of syntheses uses choline & ethanolamine from diet or from turnover of
bodys PLs. Activate the polar head group w/ CDP
PS: main pathway of synthesis is Base Exchange rxn where ethanolamine of PE is exchanged for free Serine
PC: De Novo synthesis w/in cell membranes & involves decarboxylation of PS followed by 3 methylation rxns

III. Spingolipids
A) Sphingosine
Sphingolipids are complex lipids containing a Sphingosine Backbone + Fatty Acid + Polar Head Group
Use long chain amino alcohol Sphingosine & Dihydrosphingosine rather than glycerol as alcohol portion of
molecule
Important in both plant & animal cells. They confer:
1) Blood group specifity
2) Organ & tissue Specificity
3) Tissue Immunity
4) Cell-Cell Recognition
Present in abundance in brain, Nerve Tissue

Ceramide: sphingosine w/ saturated or unsaturated long-chain Fatty Acyl Groups in Amide Linkage on amino group
w/ 2 non-polar tails it is similar in structure to diacylglycerol

B) Subgroups of SLs
Most abundant Sphingolipids in higher animals include: Sphingomyelins/cerebroside (glycoshingolipids)/gangliosides
Spingomyelins
Contain Phosphoryl-Ethanolamine or Phosphoryl-Choline as their polar head group esterified to 1-OH
of Ceramide
Since they contain phosphate, they can also be classified as PL
Glycosphingolipids
Do not contain phosphateinstead have a sugar attached by a -glycosidic linkage to the 1-OH group of
Sphingosine in ceramide
1 subgroup is the cerebrosides which contains either a galactose (Galactocerebrosides-in plasma membrane
of Neural Tissue) or a glucose (Glucocerebrosides-in membrane of non-neuronal cells) attached to ceramide
Cerebrosides contain a monosaccharide as their polar head group esterified to ceramide
Gangliosides: Most Complex
Contain Oligosaccharide head group + > residues Sialic Acid (N-acetylneuramic Acid) @ Termini
Represent 5-8% of total lipid in brain; >20 types have been identifies
Sialic Acid imparts a (-) charge to gangliosides
Nomenclature: G for Ganglioside/ w/ 1 sialic acid Gm (mono)etc. subscript numbers, letters indicate
the sequence of carb attached to ceramide
Spingolipid Synthesis
1) Sphingosine is formed from palmitoyl-CoA + Serine
2) Palmitoyl-CoA loses CoA & reacts w/ -aminoethanol derived from Serinethis requires Pyridoxal Phosphate as
Coenzyme
3) Product is reduced to Sphingosine & acylated @ the Amino Group (addition of a long chain Acyl CoA) to make
Ceramide (an intermediate precursor of sphingomyelin)
4) Terminal hydroxyl group substituted Phosphorycholine for Sphigomyelin/UDP-Glucose or UDP-Galactose for
Cerebroside/Oligosaccharide linked to ceramide via a glucose residue for Gangliosides

Note: All sphingolipids are formed from ceramide. Glycosphingolipids= ceramide +> sugar residues & they account for
5-10% of lipids of plasma membrane

C) Genetic Disorders in Metabolizing Complex Lipids
>12 genetic disorders have been identified
Lead to abnormal accumulation of certain complex lipids in specific tissues; called lipid storage diseases or
lysozomal enzyme deficienciesTypically involve the absence or deficiency of specific glucosidases
Some treatments by Enzyme Replacement Therapy: Agalsidase for -galactosidase (Fabrys) and
Imiglucerase for glucocerebrosidase (Gauchers)
Disease Enzyme Deficiency Accumulated Products Clinical Consequence
Niemann-Pick
Disease
Sphingomyelinase Sphingomyelin in Brain & Blood
Cells
Mental Retardation
Spasticity/Seizures
Ataxia
Death by age 2-3Autosomal Recessive
Fabrys Disease -galactosidase-A

(ERT: Agalsidase)
Glycolipids in brain, heart, &
kidneyresults in ischemia of
affected organ
Acroparesthesia (Severe pain in the
extremeties)
Skin lesions (angiokeratomas),
(hypohidrosis)
Ischemic infarction of kidney/heart/brain
Krabbe Disease -galactosidase Glycolipids causing destruction of
myelin-producing oligodendrocytes
Spasticity & rapid neurodegeneration
leading to death
Hypertonia, hyoerreflexia leading to
decerebrate posturing, blindness, &
deafness. Autosomal Recessive
Gauchers Disease Glucocerebrosidase

(ERT: Imiglucerase)
Glucocerebrosides in blood cells,
liver & spleen
Hepatosplenomegaly (enlarged liver &
spleen)
Anemia
Thrombocytopenia (low platelet count)
Bone pain/Erlenmeyer flask deformity of
distal femur
Autosomal Recessive in Ashkenazi
Jews
Tay-Sachs Disease Hexosaminidase-A GM2 ganglioside in neurons Progressive Neurodegeneration
Developmental Delay & early death
Autosomal Recessive in Ashkenazi
Jews
Metachromatic
Leukodystrophy
Arylsulfatase A Sulfated glycolipids (sulfatides)
accumulate in neural tissue, w/
demyelination of CNS/peripheral
nerves
Loss of cognitice & motor functions
Intellectual decline in school
Ataxia
Hyporeflexia
Seizures

Eicosanoids: Prostaglandins/Leukotrienes/Thromboxanes
Eicosanoids are paracrine hormones involved in functions essential to health & disease
Derived from C20 polyunsaturated acids (eicosanoic acids) particularly arachidonic acid
Prostaglandins: (1
st
isolated from prostate gland) contain a 5-carbon ring
Biological effects on include: cardiovascular system, blood platelets, smooth muscle, kidney & urine
formation, central & ANS, afferent nerves, endocrine system, & metabolism
Thromboxanes: (produced in platelets = thrombocytes) consist of a 6-membered ring that contains an ether
Leukotrienese: (1
st
found in leukocytes) contain 3 conjugated double bonds
Biological effects on include: WBC, lung, & blood platelets. Thought to be involved in cellular invasion
during inflammation. Likely that leukotrienes C4, D4, & E4 are slow reacting substance of anaphlaxis
(Type I hypersensitivity)
LK cause bronchoconstrictionimplicated in asthma/airway reactivity. LT receptor antagonists used
Biosynthesis: Lipoxygenase family converts arachidonic acid to variety of hydroperoxy acids (5-
HPETE)are then converted to series of leukotrienes, depending on tissue. Oxygen location varies
Source of Arachidonic Acid
Hormonal Stimulus @ membrane activates Phospholipase A2 (or by Phospholipase C + Diacylglycerol Lipase) which
releases Arachidonic Acid from C2 of Phospholipids in membrane, it is the precursor to the various eicosanoidsP-A2
is (-) inhibited by corticosteroids; prescribed for inflammation

Note:
1) Cyclooxygenase=COX=Prostaglndin H2 Synthaseoxygen is added & 5-carbon ring is formed. It is a Bi-functional
enzyme (cyclooygenase & peroxidase). (-) by NSAIDsAspirin acetylating essential Ser (irreversible inhibitor) &
Ibuprofen looks like/mimicks substrate (competitive inhibitor)
2) Type of Prostagladin formed depends on tissue; not all tissues have the capacity to make metabolites

Terpenes & Steroids
Simple lipids DO NOT contain FAs
Less abundant than Complex Lipids, they do constitute essential biomolecules (hormones/vitamins)

Terpenes: made of multiple 5-carbon isoprenes (aka isoprenoids) linked head-to-tail or tail-to-tail
Major classes
1) Fat-soluble Vitamins (A, E, K)From plants; characteristic odors or flavors-major component of essential oils
2) Ubiquinone (or Coenzyme Q) family functioning as hydrogen carriers for oxidation rxns in mito
BiosynthesisSynthesized via successive addition of C5 units

Steroids
Lipid class that are derivatives of saturated tetracylic hydrocarbon Perhydrocyclopentanophenathrene

Major Subgroups
1) Cholesterol: a sterolan alcohol that contains an OH group @ C3 of Ring A, & a branched aliphatic chain of > 8
carbons @ C17. Important component of biological membranes & also found in lipoproteins of blood plasma
2) Bile Acids: detergent-like compounds that aid in emulsification of lipids in the intestine synthesized from cholesterol
3) Hormones: cholesterol is precursor for 5 major classes of steroid hormones
Progestagens/Glucocorticoids/Mineralcorticoids/Androgens/Estrogens
4) Vitamin D-Like Compounds: important in Ca2+ & phosphorous metabolism. Derived from cholesterol via action of
light on skin. 7-dehydrocholesterolCholecalciferol (active Vitamin D3)
Biosynthesis of Cholesterol
All 27 carbons atoms are derived from Acetyl CoA.
Acetate (C2)Mevalonate (C6)Isopentenyl Pyrophosphate (C5)Squalene (C30)Cholesterol (C27)

1) 1
st
stage of synthesis: formation of Isopentenyl (C5) from Acetyl CoA
a) formation of 2-hydroxy-3-methylglutaryl CoA (HMG CoA) from Acetyl CoA + Acetoacetyl CoA
b) HMG CoA Reductase reduces HMG CoA to Mevalonate this is the Committed/Rate-limiting/Regulated
step in cholesterol biosynthesisgreat drug target
c) Regulation of HMG Reductase
1) Feedback inhibition: Cholesterol is a feedback inhibitor (-)
2) Hormonal Regulation: Glucagon causes phosphorylation & inactivation of HMG CoA Reductase
3) Sterol-mediated Regulation of Transcription: cholesterol synthesis is regulated by the amount of cholesterol
taken up by the cell during lipoprotein metabolism
Statins
Competitive inhibitors of HMG CoA Reductase used to control plasma Chol levels. Long-termreduced MIs & strokes

2) Mevalonate is then converted to Isopentenyl Pyrophosphatevia 3 consecutive phosphorylation steps followed by
a loss of CO2 & Pi
3) Synthesis of Squalene initiated via Isomerization of Isopentenyl Pyrophosphate
4) Final Stage of Synthesis consists of
Squalene Epoxide formed in a rxn utilizing O2 & NADPH via Squalene Monooxygenase
The epoxide is cyclized to lanosterol by a cyclase w/ formation of 4 rings & 4 new C-C bonds
Lanosterol is converted to cholesterol via series of rxns resulting inremoval of 3 methyl groups, Reduction of
1double bond by NADPH & the migration of another double bond

Control of Cholesterol Metabolism
1) Liver & Intestine
Cholesterol can be obtained from the diet or it can be synthesized de novo. Liver (primarily) & intestine
(secondarily) are major site of synthesis
Synthesis depends of dietary cholesterol. Feedback regulation is mediated via changes in activity of HMG
CoA ReductaseDietary cholesterol suppresses the enzyme synthesis & the intrinsic activity of enzyme
present via feedback inhibition
2) Non-liver & Non-intestine
Other cells get cholesterol mainly from plasma but can do some de novo synthesisthe primary source is LDL
a) Apo B-100 & Apo-E on the LDL surface bind to receptor on the plasma membrane of non-hepatic cellsthese
receptors are located in specialized membrane domains coated pits, containing Clathrin
b) the LDL receptor complex is internalizes via endocytosis & forms an endocytic vesicle
c) the vesicle fuses w/ lysosome & the LDL protein & cholesteryl esters are hydrolyzedthe LDL receptor is
recycled to plasma membrane
d) the released unesterified cholesterol can be used for membrane biosynthesis or esterified for storage inside the cell
by activating Acyl CoA-cholesterol Acyl Transferase (ACAT)transfers fatty acyl from fatty acyl CoA to
cholesterol
LDL receptor synthesis is subject to feedback regulation since its gene contains a sterol regulatory element that
controls the rate of mRNA synthesisso, Cholesterol causes down-regulation of LDL receptor synthesis

3) Diseases Related to Control of Cholesterol Metabolism
Familial Hypercholesterolemia/Hyperlipidemia (Type II a/b) marked elevation in plasma cholesterol
Due to: 1) deficiency or absence of functional LDL receptors; or 2) a defect in the internalization of the LDL receptor
Affected individuals have deposits of cholesterol in: skin/tendons/arteries
Genotypes: Homozygotes680 mg/dl in plasma cholesterol Heterozygotes 300 mg/dl Normals 175 mg/dl