LIPID METABOLISM Pancreatic enzymes Micelles ferry the digested fat to the Anabolic : increase synthesis of TGL,

Cholesteryl ester hydrolase surface of microvilli glycogen and protein

concentrated sources of energy (9.45 - Colesterol +FFA Fat diffuse out of the micelles into the Glucose is the major fuel
kcal/g) Phospholipase A2: removes FA at C2: interior of the intestinal cells Respiratory quotient (CO2 produced/O2
other functions include: - lysophospholipid + FFA consumed) : 1 (fasting : 0.8)
1) provide means whereby fat-soluble Lysophospholipase : removes FA at C1 Micelles Insulin controls uptake of glucose into
nutrients (e.g., sterols, vitamins) can - Glycerylphosphoryl base Increase the molecules accessible to muscle and adipose
be absorbed action of enzymes Uptake of glucose to liver : independent
2) structural component Phospholipase A2 Allows diffusion of the products of of insulin
3) components of hormones and release fatty acids from the second digestion thru aqueous lumen and come Liver
precursors for prostaglandin synthesis carbon of glycerol in contact with the epithelium and Takes up CHO, lipids and most of AA
- mammalian tissues penetrate thru lipid bilayers Distribution center: smooths out
Digestion and Absorption of lipids - insect and snake venom potentially broad fluctuations in
- Venom: has melittin which is a Absorption of fats : in the duodenum availability of nutrients for the
Fat content of diet stimulant of PLA2 and transported into the lymphatic peripheral tissues
Dietary lipids: 60 to 150g/day arachidonic acid is released from system Retains most of glucose (60%) from
>90% TGL the phospholipid membrane diffuse across the plasma membrane of portal
Cholesterol, Cholesterol Esters, disproportionately (inflammation the enterocyte Increased
Phospholipids, FFA and pain) Phosphorylation; glucokinase (high Km)
are presynaptic neurotoxins which cholesterol in the small intestine Glycogen synthesis(glycogen synthase)
TGL: serve as the major energy reserve inhibit neuromuscular transmission - dietary cholesterol HMP (5-10% 0fn glucose metab) ;inc
Digestion by blocking acetylcholine release - from the liver (bile) use of NADPH for lipogenesis
- Duodenum / jejunum from the nerve termini - half is typically absorbed Glycolysis: significant only at this time
Bile salts - rest is eliminated in the feces Increased
micelles to microvilli for Lysophospholipid glycolysis
absorption 1 acyl Intestinal cells: Stimulation by insulin of PFK, Pk
Bile salts are reabsorbe in In metabolism and interconversion of Resynthesis of TGL and CE Acetyl CoA is used for TCA or FA
terminal ileum phospholipids packed into chylomicrons synthesis
Resynthesis to TGL In oxidized lipoproteins - Apoprotein B-48 (synthesized Decreased
Pack into chylomicrons In promoting atherosclerosis Intestinal cells) Gluconeogenesis
Expcytosis into lymph - Absence : accumulation in cells Pyruvate carboxylase (in
Emulsification as aid to digestion congenital abetalipoproteinemia gluconeogenesis) is inactive
Enzyme digestion Stomach : mechanical - Apo E and C-II transferred from HDL F-1,6 biphosphatase (gluconeogenesis)is
Stomach Duodenum: - Deficient C-II typeI inactive
negligible bile salts hyperlipedemia Increased
Lingual lipase Lecithin AA degradation
- Stomach, slow, negligible peristalsis Chylomicrons : lymphatic Excess AA ; from synthesis of proteins
- only TGL at lipid-water interface Bile form micelles around the digested Short and medium chain TGL and N- molecules
(not emulsified) fat /butterfat : to portal circulation Released into circulation
Gastric lipase blood lipids: 45% P-lipids, 35% Deaminated
- Short chain TGL (milk) infants Aid to digestion triglycerides, 15% cholestrol esters, 5% Carbon : TCA or FA synthesis
Intestines Hormonal control free FAs Brancehed chain AA (leucine, Ile, val)
95 -99% occurs Cholecystokinin unchanged and prefernetially
Emulsification - Duodenum and jejunum Lipid metabolism metabolized in muscle
- Property of bile - Stimulus: lipids; partly digested - FA Protein synthesis
- Mechanical mixing by peristalsis proteins - Cholesterol Replacement of degraded proteins
- Pancreatic lipase : - Effect: Fat
Reaction at oil water interface contraction of GB: Release bile Metabolism of Fatty acid Increased
on C1 and C3 of TGL; Release of enzymes by pancreas Fed state FA synthesis
2,monoglyceride +FFA Dec. gastric motility, emptying Fasting state Liver : primary site for de novo ; occurs
<25% completely digested Secretin Fed state because dietary intake exceeds energy
- Colipase: anchor and stabilize - Intestine Absorptive state: 2-4 hours after meal expenditure
lipase at aqueous interface - Stimulus: chyme low pH Increase in plasma glucose, AA and TGL Availability of substrates : acetyl CoA,
- Release of HCO3 from pancreas (chylomicrons) NADPH
 Activation of acetyl CoA carboxylase De Novo synthesis from acetyl CoA from Glycerol is always phosphorylated on Congenital absence of C acyltransferase
( which forms malonyl CoA from acetyl CHO or AA (adipose and liver) sn-3 by glycerol kinase in skeletal muscle
CoA) TGL from diet: Glycerol-3-phosphate Myoglobulinemia , weakness following
TGL synthesis Hydrolysed Chief source of energy in catabolism of exercise
Available: Acetyl CoA (from de novo, FFA : FA Beta oxidation
hydolysis of TGL of chylomicron Source of energy acetyl CoA Successive cleavage with release of
remnants) Formation of TGL 2-carbon units successively removed acetyl CoA (2 carbon at a time) from
G-3-P from glycolysis Glycerol from carboxyl end of FA carboxyl end
Packed as VLDL Almost exclusively by liver to form Enter CAC Cleave between a(2) and B (3) carbons
Fasting state glycerol-3-P can not use FA Enzyme : FA oxidase
Increase glycolysis Brain, RBC, adrenal medulla Complex of several enzymes
Plasma FFA Gluconeogenesis (DHAP) Beta oxidation Acyl CoA DH, Enoyl CoA hydratase, B-
Decrease Fates of FA 2 carbons are cleaved at a time from Hydroxyacyl CoA DH, Acyl CoA
Glucose in portal oxidized to acetyl CoA acyl CoA molecules at carboxyl end acyltransferase (thiolase)
Insulin decreases Oxidized to CO2 and H2O Break between the a-C and B-(3)-C MM or IMM
Glucagon increases Precursor for cholesterol and steroids B-oxidation Reactions : 4 steps
Liver In liver, form ketones (prolonged Step 1 cycle produces
Inhibits glycogen synthase fasting) Actvation of FA single molecules of FADH2, NADH
Activates glycogen phosphorylase in Esterified with glycerol Only step that requires ATP acetyl-CoA
liver TGL main fuel reserve Acyl CoA synthase (thiokinase) a fatty acid shortened by two carbons
Release glucose (G-6-phosphatase) for adipose LCFA : cytosol 1. Removal of 2 H from a- and B-
brain and RBC FA oxidation SCFA: In ER, mitochondia Carbons
Muscle FA B-oxidation 2. Transport of Facyl CoA to Acyl CoA-DH
Oxidation of FA produces acetyl CoA Not a simple reverse of synthesis mitochondria 2-trans-enoyl-CoA + FADH
which inhibits pyruvate DH; and causes mitochondria LCFA/LC acyl CoA (Double bond at 2)
accumulation of pyruvate then alanine; Mitochondria Transport : by Carnitine shuttle 2. Saturate double bond with H2O
Exported to liver Utilizes NAD,FAD carnitine-acylcarnitine translocase -2enoyl-CoA hydratase
AA for exprt to muscle Generates ATP exchange transporter 3-OH acyl CoA
Pyruvate (gluconeogenesis) Aerobic Outer surface of IMM : 3. Dehydrogenation of 3-OH on the 3-C
Adipose Increased oxidation occurs: Carnitine palmitoyltransferase (carnitine L(+)-3 hydroxyacyl-CoA DH
Increase in glucagon/decrease insulin Starvation acyltrnsferase 1) in the OMM converts 3-ketoacyl-CoA + NADH
Inhibit lipogenesis DM LC acyl CoA to acylcarnitine 4. Splitting of 3-keto acyl CoA at 2 and
Inactivation of lipoprotein lipase When impaired may lead to Transported 3 position
Activation of intracellular H-sensitive hypoglycemia Carnitine palmitoyltransferase-II in the Thiolase
lipase Release of Free FA inside of IMM catalyzes acetylcarnitine + Acetyl CoA + new acyl CoA (2 C
Release of glycerol (gluconeogenesis- Breakdown of TGL in adipose CoA to form acyl CoA (mitochondrial shorter)
liver) Hormone sensitive lipase matrix) F Acyl CoA reenters the pathway
FFA : as fuel (liver, heart, skeletal FFA and glycerol Carnitine shuttle Until 4-C acyl, which is split to 2
muscles) Glycerol is released into blood and Transfer of acyl from cytosolic CoA to molecules
FFA oxidation utilized by: liver and kidney ( active carnitine (carnitine acyltransferase I) on For odd numbered chain
Muscle : B-oxidation can not meet glycerol kinase) outer surface of IMM forming O- 3-carbon residue (propionyl-CoA)
energy requirements FFA : converted to acyl CoA (acyl CoA acylcarnitine Converted to succinyl-CoA (CAC,
Ketones synthease) Transport across the membrane therefore the only part that is
Liver diffuse out into plasma (when Transferred to CoA ( carnitine glucogenic)
Greater capacity for b-oxidation lipolysis is more than reconvertion) acyltransferase II) on inner surface of Stoichiometry : B oxidation
Forms excess acetyl CoA Lipolysis and reesterification are IMM Each cycle
Used for synthesis of ketones (major continuous in adipose Carnitine acyltransferase I FADH and NADH
fuel for skeletal and heart muscle; and hormones stimulate lipolysis carnitine-acylcarnitine translocase Transported to respiratory chain : 4 ATP
can meet brains requirement) Eoinephrine, gucagon, ACTH, TSH, GH, Carnitine acyltransferase-II Palmitate
Liver and muscle glycogen : exhausted vasopressin Inhibitor of shuttle 7 cycles
after 18 hours of fast Adipose lack active glycrol kinase Malonyl CoA inhibits C acyltransferase I 7 x 4 ATP = 28
Metabolism of FA Transported to liver Malonyl CoA is building block of FA 8 molecules of acetyl CoA
Sources of FA Used to form TGL (when FA synthesis is occurring the new To CAC (10/cycle)
Diet Converted to DHAP (glycerol DH) for FA cannot be transferred to matrix) 8 x 10ATP = 80 ATP
glycolysis/gluconeogenesis
 Total : 108 less 2 for initial activation :
106
C16
7 cycles
B-oxidation in peroxisomes
Oxidise very long FA (C20)
Does not act on short; ends at octanoyl-
CoA
Products: acetyl CoA and H2O2
(hydrolyzed by catalase)
(from flavoprotein-linked DH step)
Not linked to ATP production
Induced by high fat diet (drugs as
clofibrate)
Octanoyl and acetyl CoA are further
oxidized in mitochondria
Peroxisomes
B-oxidation of Side chain (shorten) of
cholesterol in bile acid formation
In synthesis of ether glycolipids,
cholesterol and dolichol
Oxidation of unsaturated FA
Modified B-oxidation
Enzymes of B-oxidation up to double
bond (3cis-acyl-CoA or 4 cis acyl CoA)
Isomerization (delta3cis to d2-trans-
enoyl-CoA isomerase)
Delta 2 trans-enoyl CoA
Subsequent Hydration and oxidation
4 cycles of B-oxidation to acetyl CoA
4cis enoyl converted to 2 trans 4 cis
dienoyl CoA (acyl CoA DH)
To 3 trans-enoyl CoA (reductase)
2-trans enoyl CoA (isomerase)
2 trans enoyl CoA
is a substrate for enoyl CoA hydratase,
the second enzyme of beta-oxidation
4 cycles of B-oxidation
(5) acetyl CoA
Oxidation of unsaturated FA provides
less energy
Fewer reducing equivalents
3 forms of fatty acyl DH specific for
(mitochondria)
Short, medium and long chain FA
Meedium chain length acyl CoA DH
deficiency :in 1/10,000 births; said to be
more prevalent than phenylketonuria
Decrease in FA oxidation and severe
hypoglycemia
Linked to 10% cases of SIDS
Propionyl CoA
From Odd numbered FA
From certain AA
Prionyl CoA carboxylated to form
methylmalonyl CoA (propionyl CoA
carboxylase ; biotin)
Rearranged to succinyl CoA
(methylmalonyl CoA mutase; vit B12-
deoxyadenosylcobalamin)
Vit B12 defficiency: propionate and
methylmalonate are excreted in urine
May result in acidosis developmental
retardation
FA synthesis
Sources
From CHO and protein
Mammal : primary substrate: glucose
Ruminants : acetate
Sites:
Primary sites:Liver,lactating mammary
gland
Adipose and kidney, brain, lung
Increased :
Prolonged CHO diet
Fat free diet
FA synthesis
Cytosol
Organs: liver,lactating mammary gland
(adipose tissue and kidney)
Substrate: acetyl CoA
Enzyme
Fatty acid synthase complex
2 dimer with 7 enzyme activities each)
4-phosphopantetheine
in prokaryotes separate protein called
acyl carrier protein
in eukaryotes: forms a domain in the
complex
Carries acetyl and acyl units
Cofactors: NADPH, ATP, Mn,biotin,
HCO3
Pyruvate from glycolysis enters
mitochondria
1. transfer of acetyl from mitochondrial
acetyl CoA
Sources:
Pyruvate
FA oxidation
Ketones
AA
Condensation of OAA and acetyl CoA
(citrate synthase) to form citrate
Citrate can cross to the cytosol
Transfer of citrate from the mitochodria
occurs:
Increased citrate
Inc ATP inhibits iocitrate DH (oxidative
decarboxylation of isocitrate, producing
alpha-ketoglutarate)
Cytosol
Citrate acetyl CoA + OAA (citrate
lyase)
Pyruvate can regenerate acetyl CoA
2. formation of malonyl CoA from acetyl
CoA
Carboxylation of acetyl CoA (acetyl CoA
carboxylase; ATP)
irreversible
Regulated step
Activated: citrate
Inactivated: malonyl CoA, palmitoyl CoA
Phosphorylation (inactive)
Epinephrine
Dephosphorylation (active)
insulin
Insulin activates phosphatase
Epinephrine activates kinase
Long term regulation of CoA carboxylase
Increase in enzyme synthesis/ FA
synthesis
Prolonged consumption of high CHO
and fat free diet
Decrease in FA synthesis
High fat diet
Fasting
This may also regulate FA synthase
Means of transferring equivalents from
extramitochondrial NADH to NADP
Synthesis of malonyl CoA
Acetyl CoA carboxylase : regulated step
synthesis of malonyl-CoA is the first
committed step of fatty acid synthesis
(+ insulin)
Contains: biotin carboxylase, biotin
carboxylase carrier protein,
transcarboxylase
2 steps
Carboxylation of biotin
Transfer of carboxyl to acetyl CoA to
form malonyl CoA
FA synthesis
Successive addition of 2 carbon of the 3
from malonyl
FA synthase
dimer
7 enzyme activities
Domain that binds
4phosphopantheteine (known as Acyl
carrier protein (ACP) (-SH)
Cysteine residue (also with SH)
CoA also has phosphopantetheine;
carries acetyl and acyl on the terminal
thiol SH
1. acetate is transferred from acetyl CoA
to SH of ACP
Forms acetyl-S-ACP + CoA
Acetyl CoA-ACP transacylase
2. The 2 C (acetyl) is transferred to the
cyseinyl residue of the enzyme(-SH of
ACP)
Acetyl-S-enzyme + ACP-SH
3. Vacant ACP accepts 3 carbon from
malonyl CoA
Malonyl S- ACP + CoA
Malonyl CoA-ACP transacylase
4. acetyl group attacks malonyl (loses
CO2 which was added by acetyl CoA
carboxylase)
Malonyl-S-ACP + acetyl-S-enzyme
acetoacetyl-S-ACP + CO2
B-ketoacyl-ACP synthase
Condensation
acetoacetyl ACP
-Ketoacyl-ACP synthase
Convert keto to saturated acyl group
5. keto is converted to alcohol
Acetoacetyl-S-ACP + NADPH +H B-
OH-butyryl-ACP + NADP
(B-ketoacyl-ACP reductase)
6. H2O is removed to form double bond
crotonyl-S-ACP + H2O
(RCH2CH=CHCO-ACP)
B-OH acyl-ACP-Dehydrase
2nd reduction
Crotonyl-S-ACP +NADPH H butyryl-S-
ACP
Acyl-ACP
Enoyl-ACP reductase
End of cycle
Butyryl ACP is the end of the cycle
Elongation of the growing chain
Acyl is transferred to cysteinyl -SH
Butryl-ACP then condense with another
malonyl-CoA to start the second cycle
CO2 is released
Final product: 16 carbon saturated FA
Hydrolysis releases FA
Palmitoyl-S-ACP + H2O palmitate
Palmitoyl thioesterase
8 acetyl CoA + 14 NADPH +14 H + 7
ATP
Palmitic acid + 8 CoA + 14
NADP + 7 ADP + 7 pi + 7 H2O
 All C passed thru malonyl CoA except Double bonds can be introduced at C4, Remove P group to form Plasma lipoprotein
the 2 from acetyl CoA, found at the 5, 6, and 9 Diacylglycerol Phospholipids
methyl end Fatty acid desaturase: removes two Glycerol, 2FA Glycerol backbone : Phosphoglycerides
Source of NADPH hydrogen atoms from a fatty acid, Add 3rd FA to form triacylglycerol Sphingosine backbone : Sphingomyelin
HMP : 2 from1 mol of glucose creating a carbon/carbon double bond Glycerol, 3FA Synthesis
Cytosolic conversion of malate to Trans FA: Lysophosphatidic acid Formation of phosphatidic acid :
pyruvate Partially hydrogenated vegetable oil; Glycerol Simplest phosphoglyceride
NADP dependent Malate DH (malic Compete with EFA, may exacerbate EFA Phosphate Precursor of phosphoglycerides
enzyme) deficiency FA Phosphatidic acid
Control of FA synthesis Structurally similar to satuated; role in Glycerol-p + acyl CoA Synthesis of phosphoglycerides
Stimulate promotion of hypercholesterolemia and acyltransferase formation of phosphatidic acid
Well fed atherosclerosis Formation of phosphatidic acid Synthesis of phosphatidyl inositol
Increase in citrate TGL Metabolism acyltransferase PA + CTP cytosine diphosphate-DAG
Sucrose intake Sources of TGL or TAG This reacts with inositol phosphatidyl
Insulin Diet Formation of triglyceride inositol
Glucose entry to cell 40% of calorie in the diet Addition of 3rd FA to phosphatidic acid Source of 2nd messengers
Activates pyruvate DH 90% of lipids in the diet Fates of TGL +ATP phosphatidylinositol 4,5
Depress Synthesis Adipose : depot fat biphosphate inositol 1,4,5
Restricted calorie Transport Liver: packed and exported as VLDL triphoshate (IP3) and DAG
High fat diet dietary TGL : As chylomicrons Hepatic TGL synthesis
Deficiency of insulin Liver TGl : as VLDL Factors that increase synthesis Synthesis of other phospholipids
Elongation Synthesis of Triglycerides Fed state Etanolamine, choline, serine
Chain lengthening Liver, adipose tissue, lactating Diet high in CHO PA DAG + Pi
Endoplasmic reticulum mammary glands, intestinal mucosal High circulating FFA DAG + CDP-ethanolmine
Add 2 carbon using malonyl CoA as cells Ingestion of ethanol phosphatidylethanolamine
donor; NADPH FA are esterified through carboxyl High concentration of insulin (low From serine by decarboxylation
FA elongase groups to glycerol glucagon) enhance FA synthesis DAG + CDP-choline
Condensation with the carbonyl group FA on Carbon 1 is usually saturated Mobilization of TGL phosphatidylcholine (lecithin)
(release of CO2) FA on Carbon 2 is usually unsaturated CHO is unavailable Methylation of p-ethanolamine (SAM)
B-keto is reduced by NADPH to B- FA on Carbon 3 either Hormonally controlled Procides FA for synthesis of CE in HDL
hydroxy group Glycerol and fatty acid are activated by Epinephrine by LCAT
Dehydration to create double bond ATP Hormone sensitive lipase : removes FA Surfactant (dipalmitoyl)
which is reduced by NADPH Glycerol 3-P from C1 or C3 Can be synthesized de novo from
Desaturation Glycerol kinase Lipase specific for monoacylglycerol glucose
O2, NADPH and cytochrome b5 G-3-P dehydrogenase from Activation of H-sensitive lipase Phosphoglycerides
Between 9-10 and between 9 and Dihydroxyacetone P By adding P by 35cAMP-dependent PA + serine phosphatidylserine
carboxyl group Acyl-CoA protein kinase PA + ethanolamne
Animals cannot put between 9 and w- Acyl CoA synthetase (thiokinase) Epinephrine activates adenyl cyclase phosphatidylethanolamine (cephalin)
carbon Glycerol phosphate: initial acceptor of Insulin and high glucose: inactivates H- PA + choline phosphatidylholine
Stearoyl CoA + NADPH + O2 = Oleyl FA sensitive lipase (lecithin)
CoA + NAD + 2H2O Sources of glycerol P Glycerol PA + glycerol phosphatidylglycerol
C18 From glucose to produce Not metabolized by adipose (lack PA + inositol phosphatidyl inositol
C18:1;9 dihydroxyacetone P glycerol kinase) Removal of FAA at either C1 or 2 from
Animals : limited desaturation Glycerol phosphate DH + NADH To the liver form G-phosphate : phosphoglyceride : results
Free glycerol by Glycerol kinase (liver) TGL lysophosphoglyceride
need : Activation of FA by fatty acyl CoA DHAP (glycolysis or gluconeogenesis) lysolecithin
essential FA synthetase FA Most abundant in most cells
Phosphatidic acid pathway To plasma and to tissues for use PC
PUFA from plants to Addition of FA to glycerol P to form Brain and NS, RBC, adrenal medulla can PE
form C20 Lysophosphatidic acid not use FA for fuel Dipalmitoyl phosphatidylcholine
Animals: Glycerol,P,FA Phospholipids component of lung surfactant
Can introduce double bond at C9 Addition 2nd FA to form Phosphatidic Components of membranes PI : reservoir of arachidonic acid in
Delta 9 desaturase acid Non membrane: membranes
ER Glycerol, P, 2FA Bile Synthesis: all cells
Lung surfactant liver (90%)
 intestines during lipid Sulfate carrier: 3 phosphoadenosine-5- LDL rec or scavenger rec As cholesterol
absorption phosphosulfate Uptake of free cholesterol from Risk for atherosclerosis
Plasmalogen : similar to PE but with Enzyme: sulfotransferase cholesterol rich lipoprtn to cell High cholesterol level in LDL
ether link at C1 of glycerol instead of NS membranes High saturated fat in diet
ester link Degradatio of sphingolipids Synthesis Deposition of cholesterol and CE in
Hydrolyzed by phospholipases Lysosomal enzymes Hydrolysis of CE artery wall
Phospholipase A1 :from C1, etc Cholesterol metabolism decrease in cell Cholesterol synthesis
Phosphlipse D releases free bse Steroids Efflux from membrane to HDL C atoms are from acetate
Sphingomyelin Isoprenoids Esterification by ACAT H : from NADPH
Membrane of nerve tissue Derived from isoprene, 5 carbon units Utilization for synthesis of other steroids Site: Cytoplasm
Sphingosine Derivatives of cholesterol Most tissue
Serine + palmitoyl perhydrocyclopentanophenanthrene Synthesis (700mg/day) Liver
Ceramide Cholesterol Liver and intestine (10% each of total Intestines
Addition of FA to the amino group of Hydrocarbon rings synthesis) Steps
sphingosine Branched hydrocarbon chain ER Synthesis of mevalonate form acetyl
Precursor : Hydroxyl Diet CoA
Sphigomyelins Sterols Present Formation of isoprenoid units from
glycolipids 8-10 C in side chain at C17 and OH at Tissues mevalonate (loss of CO2)
Esterification of Ohmethyl grp at C1 C3 membranes Condensation of 6 isoprenoid units to
with phosphorylcholine Cholesterol major sterol in animals Plasma in lipoproteins form squalene
ceramide: Cholesterol ester: FA at C3 Plasma cholesterol Cyclization of squalene to
Sphingosine B-sitosterol in plants Normal : <5.2 mmol/L lanosterol(parent steroid)
Serine Not absorbed in humans Transported: Formation of cholesterol
palmitoyl Blocks cholesterol by competetive LDL 1. synthesis of mevalonate
FA binding with intestinal cells CE 2/3 of plasma level Synthesis of HMG-CoA
Ceramide + phospatidyl choline = Cholesterol Uptake to many tissues 2 acetyl CoA acetoacetyl CoA
sphingomyelin Functions: HDL Cytosolic thiolase
Glycolipids Cell membranes Unsterified (acceptor) + acetyl CoA HMG
Derived from ceramide (sphingosine + Precursor of : Removed from tissues CoA
FA) Bile acids Forms: (HMG CoA synthase)
Monosaccharide or oligosaccharide + Steroid hormones Free cholesterol HMG CoA mevalonate
ceramide Vit D CE HMG CoA reductase + NADPH
No P group Synthesis: Transport HMG CoA syntase
Plasma membrane (nervous tissue) Liver (10%) LDL: to peripheral tissues Cytosolic: cholesterol synthesis
Cellular interactions Intestines (10%) HDL : from the tissues to the liver Mitochondrial: ketone synthesis
Antigenic Adrenal cortex Food sources: HMG CoA reductase: the rate limiting
Cell surface receptors Ovary Yolk, meat, liver, brain step in cholesterol synthesis
UDP-gal or UDP-glu + ceramide Testis May affect cholesterol level synthesis of mevalonate
Galactocerebroside, glucocerebroside placenta Increase in cholesterol ingested will Rate limiting step
CMP-NANA (sialic acid) + ceramide Regulation of cholesterol balance in liver inhibit HMG CoA Site: ER
gangliosides Dietary synth Highly saturated fat diet Reduction
Glycosphingolipids Extrahepatic increases cholesterol 15 - 25% 2 NADPH
Neutral glycosphingolipids Increase fat in liver leads to increase in Removal of CoA
Cerebrosides chylomicron remnants acetyl CoA and increase formation of Ultimate source of C : acetyl CoA
NS (myelin sheath) HDL cholesterol Mevalonate : 6 carbons
Acidic glycosphingolipids de novo synth Lack of insulin or thyroid From HMG-CoA
Gangliosides Liver Pool hormone increases cholesterol 2. Formation of isoprenoid
Most complex HDL Free chol bile Diet with highly unsaturated fat Isoprene (5) formed by decarboxylation
Ganglion cells (nerve endings) acids decreases blood cholesterol slightly to of mevalonate
Ceramide oligosaccharides + N- VLDL in bile bile moderately Isoprene : isopentenyl-PP
acetylneuraminic acid salts Decrease in diet of 100mg can decrease 3. Condensation of isoprenoid units,
Enzymes: glucosyl transferases Balance in tissues 0.13 mmol/L serum isopentenyl diphosphate;
Sulfatides increase in cell cholesterol Elimination of cholesterol isopentenyl-PP : 1 isoprene unit
Cerebrosides with galactosyl that has Uptake of cholesterol lipoprotein by 1gm / day geranyl-PP : 2 isoprene units
been sulfated receptors as bile acids farnesyl-PP : 3 isoprene units
 2 FPP condense to squalene Lovastatin, mevastatin, etc 3-hydoxy butyrate: predominant in Immediate: arachidonic acid
Squalene : 6 isoprene units Degradation of cholesterol blood and urine in ketosis All nucleated cells
Condensation reactions conversion to bile acids Acetoacetate and 3-OH-butyrate : Except lymphos
Release of Pp Secretion into bile interconverted PGG2, PGH2 (parent compound)
DPP+ IPP to form Geranlyl PP (GPP) (10 Acted upon by bacteria D(-)-3-hydroxybutyrate DH PG endoperoxide synthase complex
C) Coprostanol , cholestanol (mitochondrion) glutathione
Condensation with isopentenyl used as a biomarker for the presence of NAD PGH2 : pecursor of the PGs and
diphosphate human fecal matter Acetoacetate : spontaneous thromboxanes
Farnesyl diphosphate (15C) Bile: decarboxlation to acetone numerical subscript (1 to 3)denotes the
2 FPP squalene (30) Phosphatidylcholine and bile salts Acetyl-CoA + acetyl-CoA form total number of double bonds in the
4. cyclization of squalene Bile acids thiolase alkyl substituents,
Oxidosqualene:lanosterol cyclase Primary acetoacetyl-CoA Greek subscript ( or ) is used with
5. Conversion of Lanosterol to Cholic acid Starting point prostaglandins of the PGF series to
cholesterol chenodeoxycholic acid + acetyl-CoA describe the stereochemistry of the
Shortening to 27C Secondary bile acids 3-hydroxy-3-methylglutaryl-CoA hydroxyl group on carbon 9
Removal of 3 methyl Intestine by bacteria synthase (rate limiting) Cox 1 : in most tissues;
2 methyl at C4 Deoxycholic acid Only in liver responsible for the baseline levels of
Migration of double bond from C8 to C5 Lithocholic acid HMG-CoA prostaglandins
Lanosterol : First closed sterol ring By removing OH Acetyl-CoA split-off GI : maintains normal lining; kidney and
structure derived from squalene Intestinal bacteria HMG-CoA lyase platelet function
HMG CoA reductase : Bile acid synthesis Free acetoacetate Cox 2 :
Rate limiting step of cholesterol Hydroxylation Reduced to 3-OH-butyrate produces prostaglandins through
synthesis 7 ahydroxylase: rate limiting at C7 HMG-CoA stimulation
lovastatin, zocor, crestor, lipitor : Monooxygenase Intermediate in catabolism of leucine Primarily at sites of inflammation
cholesterol lowering drugs; NADPH, cytochrome 450 Precursor of cholesterol PGH2 : parent
competitively inhibit HMG-CoA Reduction Acetoacetate 3 forms of PG E synthases
Reductase cholesterol synthesis in Shortening of HC tail by 3C may be used in cholesterol synthesis in The most important is: a cytosolic
cell LDL receptors circulating Conjugation cytosol enzyme expressed constitutively in
LDL peroxisomes Acetacetate receives CoA from succinyl many different types of cellS and linked
HMG-CoA in ketogenic pathway with glycine and taurine CoA functionally to COX-1 to promote
HMG-CoA synthesis occurs in the Bile salts Acetoacetyl CoA immediate formation of PGE2
mitochondria Addition thru amide bond: Thiophoase PGI : formed in endothelial and smooth
serves as a substrate for HMG-CoA glycine Succinyl-CoA-acetoacetateCoA muscle cells
Lyase to produce acetoacetate Glychocholic acid transferase TXA : platelets and lung, respectively
HMG-CoA formation in cholesterol Glycochenodeoxycholic acid 2 acetyl CoA TXA2
synthesis : occurs in cytoplasm Taurine; thiolase Primarily by platelets
HMG-CoA reductase in ER Taurocholic Ketonemia : due to icreased production Paltelet aggregation, Decrease
HMG CoA reductase Taurochenodeoxycholic acid rather than dec in utilization cAMPVasoconstriction
Membrane protein of ER Ketogenesis occurs : high rate of FA Acetone: volatilized in the lungs Contraction of sm muscle
Active in cytosol oxidation in liver Assessment of ketosis: measurement of PGE2
Rate limiting in cholesterol synth When not enough oxaloacetate is blood levels Most tissues esp kidney
Regulation available for CAC Liver can not use acetoacetate as fuel Vasodilatation
Feedback inhibition Sites: liver mitochodria Cannot convert acetoacetate to Relaxes sm muscle
By cholesterol causes: acetoacetyl CoA Used to induce labor
Hormonal High fat but low CHO intake Lacks succinyl CoA:acetoacetate CoA PGI2
Glucagon Starvation transferase (thiophorase) Endothelium of vessels
Decreases synthesis Inability to metabolize CHO (DM) Eicosanoids Vasodilatation
Inactive form Ketone bodies Prostaglandins, thromboxanes, Inhibits platelet aggregation
Insulin Acetoacetate leukotrienes Increase cAMP
Increase in synthesis B-hydroxybutyrate Extremely short life PGF2
active acetone Produced in very small amounts Prod by most tissues
Cholesterol in cells Acetoacetate: preferred fuel by heart, Act locally Vasoconstriction
Gene transcription renal cortex Elicit pyhsiologic responses Contraction of smooth muscle
By drugs brain Synthesis of Prostaglandins Stimulates uterine contraction
Competitive Inhibitors of enzyme: Dietary precursor : linoleic Lipooxygenase:
 inactive in leukocytes and in
macrophages
Response to immunologic and
nonimmunologic stimuli
LTA4
In leukocutes, plartelets, mast cells,
heart and lung vascular tissues
LTC4m D, E
Contraction of smooth muscle
Bronchocostriction
Vasoconstriction
Inc vascular permeability
SRSA
LTB4
Chemotaxis of polys
Lysosomal enzymes release
Adhesion of WBC
Glycosphingolipids
Synthesis
Addition of glycosyl monomers
transferred from sugar-nucleotide
ER
Enzymes:
Glucosyl transferase
Sulfonyltransferase
Fom sulfate carrier (3-
phosphoadeosine-5-phosphosulfate to
3OH group of galactose
Cerebrosides
Gangliosides
Sulfatides
glycosphingolipids
Degradation
Lysosomes
Last group added is the first removed
Enzymes:
A and B galactosidase
B-glucosidase
Neuraminidase
Hexosaminidase
Sphingomyelinase
Sulfatase
ceramidase
Sphingolipidosis
Hydrolases may be absent
Sphingolipids accumulate in lysosomes
Seen in nerve tissue, neurologic
deterioration
Autosomal recessive disease
Except: Fabrys (X-linked)