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LIPID METABOLISM
I. Lipid Digestion, Absorption, and Transport
Triglycerides ~ 90% of dietary lipids Metabolic NRG storage
Oxidized to CO2 and H2O
Triglyerides, cont…
oxidation state than glucose metabolism of fats yields
~9 kcal/gram vs ~4 kcal/gm Carbohydrates, proteins
Triglyceride Storage, cont…
Stored in anhydrous state Non-polar Provide ~ 6 times energy of
hydrated glycogen
Triglyceride storage, cont…
Stored in large quantities in cells Non-reactive with other cell components Segregated into lipid droplets Do not affect osmolarity of cytosol
Triglycerides, cont…
To be used as fuel: insoluble in H2O Must emulsify before lipid digestion in
intestine Must be “carried” in blood (proteins)
Triglycerides, cont…
Sources of fat Three cellular sources
Fat in diet Fat stored in cells Fat synthesized in one organ and
transported to another
Triglycerides, cont…
Fats obtained vary by organism Vertebrates
Fat in diet Fat in adipose tissue Convert excess carbohydrate to fat
in liver for export
Triglycerides, cont…
Humans Industrialized countries:
~ 40% of daily calorie consumption is fat
Should be < 30%! Atkins kills…
Humans, Triglycerides, cont…
Used for > half the energy in: Liver Heart Resting skeletal muscle
Humans, Triglycerides, cont…
Hibernating animals and migrating birds
sole source of NRG Higher plants:
Do not depend on fats for energy Germinating seeds
Lipid digestion, cont…
Digestion Triglyceride digestion
takes place at lipid-water interfaces Rate is based on surface area at
interfaces Peristalsis Emulsification by bile
Lipid digestion, cont…
Bile Synthesized from cholesterol,
biliverdin By liver Stored in gallbladder Released after ingestion of fat
Lipid digestion, Bile, cont…
Acts as digestive detergent Converts dietary fats into mixed
micelles Micelles contain bile salts and
triglycerides
Lipid digestion, cont…
Role of lipase Pancreatic lipase:
catalyzes hydrolysis of triglycerides At 1 and 3 positions sequentially Forms 1,2-diglycerol 2-glycerol Soap
Role of lipase, Lipid digestion, cont…
Phospholipase A: Pancreatic enzyme Degrades phospholipids Hydrolysis at C(2)
Absorption of Lipids
Absorption Molecules diffuse into cells of
intestine Facilitated by bile salts
Micelles transport non-polar lipids across aqueous boundary layer
Absorption, cont…
Bile salts essential Fatty Acids Fat soluble vitamins
A,D,E & K Biliary disease interferes
Lipid Uptake in Vertebrates
Role of Lipase, cont…
Reconversion: in mucosa cells Lipid digestive products
triglycerides Packaged into Chylomicrons
Lipoprotein aggregates Triglycerides, cholesterol, protein
Chylomicron
Aggregate of triglycerides, cholesterol, and proteins
Reconversion, Role of Lipase, cont…
Released into bloodstream: Via lymphatic system Lacteals
Triglycerides synthesized in liver Packaged in VLDL Directly released into blood
Role of lipase, cont…
Transport APOLIPOPROTEINS: lipid-binding
blood proteins Transport between organs
Form classes based on density
Role of lipase, cont…
Proteins on outside of Chylomicron Are apoproteins Act as cell surface receptors for
recognition (apo C-II)
Lipid Uptake in Vertebrates
Transport, Role Chylomicrons, cont…
Chylomicrons and VLDL: Move triglycerides, cholesterol To Skeletal muscle & adipose LIPOPROTEIN LIPASE
an extracellular enzyme Activated by apo C II Hydrolyzes triglycerides
Chylomicron
Carry triglycerides, cholesterol to tissues via lymphatic system (lacteals)
Transport, Role of lipase, cont…
Deletes lipoprotein from triglyceride Forms IDL Then LDL
LDL: (130-159 mg/dl) removed from plasma at liver, adrenals, adipose
HDL: (above 35 mg/dl) moves cholesterol from tissues Sends to liver for excretion in bile salts
Ratio LDL:HDL = 2:1
Lipid Metabolism, cont…
Uptake by cells FA taken in by:
muscle: oxidized for NRG adipose: stored as triglyceride
Lipid Uptake in Vertebrates
Transport, Role of lipase, cont…
Glycerol Transported to liver or kidney Converted to dihydroxyacetone
phosphate And then???
Pathway to Glycolosis
Conversion of glycerol to dihydroxyacetone phosphate
Transport, Role of lipase, cont…
Remnants of Chylomicrons triglycerides; cholesterol and
apoproteins (apo E, apo B-48) To liver
Uptake by endocytosis Triggered by apolipoproteins
Uptake in Liver via Endocytosis
Chylomicron Remnants, cont…
Triglycerides Oxidized for energy or Converted to ketone bodies
Excess fatty acid Convert to triglycerides Pack into VLDL To adipose for storage
Lipid Uptake in Vertebrates
Mobilization of Stored Fats
Mobilization of stored triglycerides Triggered by hormones
Stimulus is in blood glucose Hormones:
Epinephrine Glucagon
Mobilization of Stored Fats, Hormone Action, cont…
Activate adenylate cyclase in adipocyte plasma membrane
Increases cAMP Activates protein kinase Activates triglycerol lipase Catalyzes hydrolysis of ester bonds in
triglycerides
Mobilization of Stored Fats
Action of second messenger hormones triggers mobilization of stored triglycerides
Role of lipase, cont…
Free fatty acid released into bloodstream
Binds to serum albumin Carried to tissues
Released to diffuse into cells
Role of lipase, cont…
NOTE: Glycerol glycerol-3-phosphate dihydroxyacetone phosphate glycolysis
II. Fatty Acid Oxidation
FA activation: Free FA cannot enter Mitochondria Occurs in cytosol
Acyl-CoA synthetases (thiokinases) 3 isozymes mitochondrial membrane
FA activation, cont...
FA + CoA + ATP fatty acyl-CoA + AMP + PPi
different acyl-CoA’s work on different FA
Fatty acyl-CoA: high energy compound
Fatty acid oxidation, cont…
Transport across mitochondrial membrane: Formation of fatty acyl-carnitine
Carnitine acyl transferase I Outer face of inner membrane Fatty acyl from CoA carnitine CoA released cytoplasm
Transport across mitochondrial membrane, cont…
Acyl-carnitine/carnitine transporter Carrier Fatty acyl-carnitine matrix carnitine to inter-membrane space Facilitated diffusion
F.A. Entry into Mitochondria
Fatty acid oxidation, cont…
Transfer of acyl from Carnitine to intra-mitochondrial membrane
Carnitine acyltransferase II Inner face of inner membrane Regenerates fatty acyl-CoA Frees carnitine returns to cytosol
Carnitine Acyltransferase II, cont…
Two separate pools of CoA (ATP, NAD+)
Cytoplasm: makes FA Mitochondria: oxidative degradation
Pyruvate FA AA
ß-oxidation
ß-oxidation: FA dismembered to fatty acyl-CoA Mitochondrial oxidation of FA
Stage One: ß-oxidation Remove 2-C chunks as acetyl-CoA Begins at carboxyl end of fatty acid chain
ß-Oxidation
Fatty acids are dismembered into Acetyl-CoA subunits
Each acetyl Co-A sends 4 H to NAD, FAD
Mitochondrial oxidation, cont…
For example, 16C palmitic acid 8 acetyl CoA
Stage Two: oxidation of acetyl-CoA CO2
Stage Three:
oxidative phosphorylation
ATP (+H2O)
ß oxidation, cont…
ß oxidation: 4 reactions Formation of a trans – , ß double
bond Between C-2 () and C-3 (ß) Yields: Trans-∆2-enoyl-CoA Acyl-CoA dehydrogenase FAD 2 ATP Similar to succinate dehydration
ß-Oxidation
First: formation of double bond
Second: hydration of double bond
Third: dehydrogenation
Fourth: cleavage to Acetyl Co-A
ß-oxidation, cont…
Hydration of the double bond By enoyl-CoA hydrase Forms 3-L-hydroxyacyl-CoA Similar to fumarase reaction
ß-oxidation, cont…
Dehydrogenation By ß-hydroxyacyl-CoA
dehydrogenase To ß-ketoacyl-CoA NAD 3 ATP Similar to malate dehydrogenase
reaction
ß-oxidation, cont…
C -Cß cleavage (thiolysis) Catalyzed by ß-ketoacyl-CoA thiolase
(thiolase) Produces:
acetyl-CoA fatty acyl-CoA (2 carbons short)
ß oxidation: Enzymes in Mitochondrial membranes
3 kinds of acyl-CoA dehydrogenase Specify short, medium, long chain fatty
acid Medium-chain acyl-CoA dehydrogenase
(MCAD) Deficient in ~10% of SIDS babies More common than PKU
Sites of Mitochondrial Enzymes
ß-oxidation, cont…
Fatty acid oxidation is highly exergonic Each round of ß-oxidation
1 NADH 1 FADH2
1 acetyl-CoA
ß-oxidation, Energy Payoff
Acetyl-CoA citric acid cycle Example: PALMITOYL-CoA (16C)
7 rounds of ß -oxidation 7 NADH 7 FADH2
8 acetyl CoA So, 7 + 24 NADH = 31 x 3 = 93 ATP
7 + 8 FADH2 = 15 x 2 = 30 ATP + 8 GTP 131 hi-energy molecules
for fatty acyl CoA - 2 ATP
129 total
ß-oxidation, cont…
READ IN TEXT: Oxidation of unsaturated fatty acid:
2 additional reactions Oxidation of odd-chain fatty acid:
3 additional reactions
III. Ketone Bodies
Acetyl-CoA from ß-oxidation Enters citric acid cycle Converted to KETONE BODIES
Water-soluble “equivalent” of FA
Ketone bodies, cont…
Ketogenesis Occurs in liver:
acetyl CoA ketone bodies Primary ketone bodies
Acetoacetate - out of liver D-ß-hydroxybutyrate - out of liver Acetone - exhaled
Ketone Body Formation
Ketone bodies, cont…
Function: fuel for peripheral tissues Heart, skeletal muscle Brain
Normal fuel is glucose In starvation: ketone bodies
Enzyme production adapts over time >40 days, provide 70% energy
Ketone bodies, cont…
Production and transportation Determined by availability of
oxaloacetate Combine with acetyl group enter TCA cycle
Ketone bodies, cont…
In starvation Oxaloacetate pulled from citric
acid cycle Used in gluconeogenesis
[oxaloacetate] decreases therefore little kreb’s cycle Production of ketone bodies is
favored
Production and transportation, cont…
Overproduction: starvation, diabetes Moved from liver to other tissues
Allows fatty acid oxidation in liver In tissues:
ketone bodies converted back to acetyl-CoA
Production and transportation, cont…
Formation of ketone bodies from acetyl-CoA occurs in the mitochondrial matrix
thiolase 2 Acetyl-CoA acetoacetyl-CoA Acetoacetyl-CoA + acetyl-CoA
ß -hydroxy- ß -methylglutaryl-CoA HMG-CoA free acetoacetate + acetyl-CoA
Production and transportation, cont…
Acetoacetate D- ß -hydroxybutyrate dehydrogenase
D-ß-hydroxybutyrate Acetoacetate decarboxylase
Acetone High in uncontrolled diabetes
Production and transportation, cont…
Ketosis Pathological Acetoacetate produced too fast
for elimination Breath smells like acetone Blood pH decreases acidosis
Lipid Biosynthesis
“Reverse” of lipid catabolism Know differences
Where in the cell does each occur? What are the e- transport
molecules? What are the acyl group carriers? Where does acetyl Co-A “fit into”
each set of reactions?
Pathway Differences
Fatty Acid Biosynthesis
Read in Text For major
steps, know Type of
reaction Enzyme Product
Cholesterol Biosynthesis
Read in Text Know
Draw steps Intermediate
s