Lipid Metabolism

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Lipid Metabolism
2
Lipid Transport in Blood

• Lipids are not water soluble
• Blood is mainly water
• Pack lipids in protein
• Chylomicrons
• Made in the enterocytes (small intestine)
• Lipoproteins(lipids and proteins)
• VLDL, LDL, HDL made in liver

Groff Gropper, 1999
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Release of Lipids at Liver

• Chylomicrons ? chylomicron remnants
• Cholesterol-rich
• Taken up by liver and fatty acids are metabolized

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Repackaging in the Liver

• Lipid is repackaged in the liver to VLDL or very
  low density lipoprotein
• Lipoproteins are classified by density
• Lipoproteins transport lipid to the rest of the
  body

TG
TG
VLDL
LDL
HDL
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Lipoproteins

• Classified by density
• Proteinlipid ratio
• More protein, increased density
• More lipid, decreased density
• Four classes of lipoproteins
• Chylomicrons
• VLDL
• LDL
• HDL

Formed in liver
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Lipoproteins

• Differ according to the lipidprotein ratio
• Density
• Chylomicrons
• Very-lowdensity lipoproteins (VLDL)
• High lipid content
• Low-density lipoproteins (LDL)
• Main cholesterol transport
• High-density lipoproteins (HDL)
• Low lipid content

Low
High
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aTriacylglycerols, bPhospholipids, cCholesteryl
esters, dFree cholesterol, eFree fatty acids
HDL2 and HDL3 derived from nascent HDL as a
result of the acquisition of cholesteryl esters
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Low Density Lipoproteins

• VLDL ? ? LDL
• Cholesterol-rich
• Converted to bile salts
• Carries cholesterol to tissues
• Used for membrane synthesis
• LDL bad cholesterol
• Associated with plaque formation in blood vessels
• High triglyceride and cholesterol content

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High Density Lipoproteins

• Removes cholesterol from
• Cells
• Lipoproteins
• Deliver cholesterol to liver for excretion
• Converted to bile salts and excreted in feces
• HDL good cholesterol
• Is cholesterol bad for you?
• Cell membranes, bile salts, synthesis of steroid
  hormones
• Ratio of LDLHDL vs. total cholesterol

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Lipid Transport

• Free fatty acids transported as complex with
  albumin in blood
• Lipids rapidly removed from blood
• Liver
• Fat depots
• Other tissue

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Release of Lipids From Lipoproteins

• Lipoprotein lipase (LPL)
• Enzyme anchored on the cell membranes in blood
  vessels
• Releases glycerol and free fatty acids from
  chylomicrons and lipoproteins
• Glycerol and free fatty acids absorbed by cells
• Muscle (oxidized as a source of energy)

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Lipolysis Monogastric Ruminant

• Mobilization of body triglycerides for use as
  energy

Lipoprotein Lipase

Triglyceride
Glycerol
3 FFA

Gluconeogenesis
?-oxidation
Glycolysis
Free fatty acids bind to albumin to form
non-esterified fatty acids that are soluble in
blood
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Triglyceride Catabolism

• Hydrolysis of triglycerides yields
• One glycerol
• Three FFA
• Glycerol is used for energy or gluconeogenesis
• Glycerol enters glycolytic pathways
• FFA are oxidized to CO2 and H2O
• ?-oxidation
• Takes place in mitochondria
• FAs cannot be used for gluconeogenesis

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Beta Oxidation
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ß-oxidation Saturated Fatty Acids

• Cleaves two carbons at a time from the carboxyl
  end
• Produces NADH, FADH2 and acetyl-CoA
• Acetyl-CoA enters TCA cycle
• NADH and FADH2 enter electron transport chain
• Yield ATP

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1st Step in Beta-Oxidation
Activation Use 2 ATP equivalents to attach CoA
Oxidation FAD takes H, Creates new double bond
between C 2 3 Hydration add water across
double bond Oxidation NAD takes Hs, new O
formed Addition Cleavage Add new CoA, cleave
off acetyl-CoA. Lose 2 C
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?-Oxidation
1st
2nd
3rd
4th
5th
6th
last

• Palmitate (160)
• Carboncarbon cleavage
• 1 FADH2 1 NADH ? 5 ATP (via electron transport
  chain)
• 7 cleavage points x 5 ATP 35 ATP
• Oxidation of acetylCoA
• 8 acetyl-CoA units entering TCA cycle x 12 ATP
  96 ATP
• Total ATP ? 35 96 131 2 ATP 129 ATP
• 2 ATP used for fatty acid activation and entry
  into mitochondria

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Summary of ß-oxidation
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Special Considerations

• Why doesnt muscle utilize fatty acids during
  exercise?
• Requires oxygen available for oxidation
• Use anaerobic fermentation of glucose to lactate
  preferentially
• Why dont red blood cells utilize fatty acids for
  their energy metabolism?
• No mitochondria in RBCs

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Unsaturated Fatty Acids

• Unsaturated fatty acids must be saturated before
  beta-oxidation
• Isomerase converts cis to trans and moves double
  bond to the 2 position
• In polyunsaturated need reductase
• Add Hs to second double bond

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Odd Chain Fatty Acids

• Minor species, odd chains made by microbes,
  degradation of AAs
• B-oxidation occurs to end
• Left with 3 carbon CoA (propionyl CoA)
• Vitamin B12 cobalamin co-enzyme
• Catalyzes conversion of propionyl CoA (3 C) to
  succinyl-CoA (4 C)
• TCA cycle intermediate

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Ketone Bodies (Ketogenesis)

• Acetone, acetoacetate, ß-hydroxybutyrate
• Produced in liver from incomplete oxidation of
  fatty acids
• Used by extra-hepatic (non-liver) tissue in
  preference to fatty acids as energy
• Turned into acetyl-CoA
• Excess spills over into urine or exhaled as
  acetone

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Metabolism of Fats
Metabolism of natural C20 cis fatty acids
produces powerful eicosanoids
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Cyclooxygenase (COX) Inhibitors

• Cyclooxygenase has 3 isoforms (COX-1, COX-2, and
  COX-3)
• Non-steroidal anti-inflammatory drugs (NSAIDs)
  inhibit these pathways
• Aspirin and ibuprofen are classic examples
• Acetaminophen is NOT an NSAID because it does not
  inhibit inflammatory pathways
• Specifically inhibits COX-3 which produces
  prostanoids in the brain so it blocks the
  perception of pain

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Fatty Acid Synthesis

• In fed state - lots of glucose
• Glycogen stores fill up
• ATP and citrate inhibit glycolysis pathways
• Glucose diverted through the pentose-phosphate
  pathway
• NADPH formed and used in fatty acid synthesis
• Pyruvate is formed

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Fatty Acid Synthesis - Monogastrics

• What are the advantages of storing excess feed
  or energy as fat?
• High energy density tissue, low water content
• Major producers of fatty acids
• Liver
• Adipose tissue
• Mammary gland
• Can animals synthesize all fatty acids?
• NO essential fatty acids MUST come from diet
• C182, C183
• Cats cannot synthesize C204

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Fatty Acid Biosynthesis - Monogastric

• Occurs in endoplasmic reticulum
• Occurs when
• Energy needs are met (ATP gt ADP)
• Glycogen stores full
• Excess nutrients present

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Fatty Acid Biosynthesis - Monogastric

• Begins with acetyl-CoA from
• Carbohydrate metabolism (glucose)
• Specific amino acids
• Degraded lipids
• Fatty acid chains are created
• 2C units added from carboxyl to methyl end
• Ester bonds
• Up to 16C (palmitate) fatty acids can be
  synthesized
• NADPH required as energy source

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Acetyl CoA
TCA Cycle
Citrate
Mitochondria
Cytosol
Citrate
Oxaloacetate
HCO3 ATP
(2C) Acetyl CoA
(3C) Malonyl CoA
Acetyl CoA Carboxylase (biotin)
CO2
Fatty Acid Synthase
NADPH
4C Butyryl CoA
2C Acetyl CoA
3C Malonyl CoA
CO2
NADPH
6C Caprayl CoA
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Fatty Acid Biosynthesis - Monogastric

• Cycle continues by continued addition of malonyl
  CoA and loss of CO2
• Palmitate (16C) is final product after 7 cycles
• Desaturation and elongation occur elsewhere ER

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Fatty Acid Modifications

• Palmitate can be elongated
• Addition of two-carbon units at COOH-end of fatty
  acid
• Desaturation
• C160 and C180 can be converted to C161 and
  C181, respectively

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Why are w-3 w-6 Essential?

• Mammals lack enzyme to add double bonds beyond
  C-9
• Chain elongation and double bond addition yield
  arachidonic acid (C204) from linoleic acid
  (C182)

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Lipid Synthesis in Monogastrics
Figure 25.10
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Lipogenesis - Ruminants

• Similar to monogastrics except for
• Sources of carbon (acetyl-CoA)
• Acetate
• Lactate
• Beta-hydroxy-butyrate
• Dietary fatty acids
• Unable to convert glucose to fatty acids

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Adipose Tissue

• Adipocytes are the major storage site for
  triglycerides
• Adipose tissue (stored for later use, or
  immediately oxidized as a source of energy)
• Contains up to approximately 85 lipid
• Contains approximately 90 DM
• What is the DM content of muscle?
• Only 20-25 DM!!!

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• Change in size amount of fat stored
• Obesity increase in both size and number
• MS, Lupus other diseases normal tissue dies,
  replaced by fibroblasts, become adipocytes

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Adipose Tissue
Fed state...
Groff Gropper, 1999
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Adipose Tissue

• Fasted state
• Blood glucose level decreases ? insulin levels
  decrease and glucagon levels increase
• Lipolytic activity increases
• Hormone-sensitive lipase
• Release of fatty acids
• Free fatty acids released into blood
• Free fatty acidalbumin complex
• Liver takes up free fatty acids
• Oxidation or formation of ketone bodies

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Leptin

• Protein hormone produced by adipocytes
• Larger cells more leptin produced
• Effects on many tissues
• Hypothalamus
• Regulates eating behavior
• Negative-feedback mechanism

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Leptin-deficient mutants (left) fail to limit
their eating and becomes 3 times the weight of
normal mouse (right)