Download - Lipid Metabolism
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
Release of Lipids at Liver
Chylomicrons chylomicron remnants
Cholesterol-rich
Taken up by liver and fatty acids are metabolized
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
VLDL
TG
LDL
TG
HDL
Lipoproteins
Classified by density
Protein:lipid ratio
More protein, increased density
More lipid, decreased density
Four classes of lipoproteins
Chylomicrons
VLDL
LDL
HDL
Formed in liver
Lipoproteins
Differ according to the lipid:protein ratio
Density
Chylomicrons
Very-low–density lipoproteins (VLDL)
High lipid content
Low-density lipoproteins (LDL)
Main cholesterol transport
High-density lipoproteins (HDL)
Low lipid content
Low
High
Complex Source Density
(g/ml) %Protein %TGa %PLb %CEc %Cd %FFAe
Chylomicron Intestine <0.95 1-2 85-88 8 3 1 0
VLDL Liver 0.95-
1.006 7-10 50-55 18-20 12-15 8-10 1
IDL VLDL 1.006-
1.019 10-12 25-30 25-27 32-35 8-10 1
LDL VLDL 1.019-
1.063 20-22 10-15 20-28 37-48 8-10 1
*HDL2
Intestine,
liver
(chylomi
crons
and
VLDLs)
1.063-
1.125 33-35 5-15 32-43 20-30 5-10 0
*HDL3
Intestine,
liver
(chylomi
crons
and
VLDLs)
1.125-
1.21 55-57 3-13 26-46 15-30 2-6 6
Albumin-FFA Adipose
tissue >1.281 99 0 0 0 0 100
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
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
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 LDL:HDL vs. total cholesterol
Lipid Transport
Free fatty acids transported as complex with albumin in blood
Lipids rapidly removed from blood
Liver
Fat depots
Other tissue
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)
Lipolysis – Monogastric & Ruminant
Mobilization of body triglycerides for use as energy
Triglyceride Glycerol 3 FFA +
Lipoprotein Lipase
Glycolysis
Gluconeogenesis Β-oxidation
* Free fatty acids bind to albumin to form non-esterified fatty acids that are soluble in blood
*
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
FA’s cannot be used for gluconeogenesis
β-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
O
CH3–C–CoA
=
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 H’s, new O= formed
Addition & Cleavage: Add new CoA, cleave off acetyl-CoA. Lose 2 C
C1C2C3C4C5
C6C7
C8C9
C10C11C12C13C14C15
C16
CoA
O
O
-Oxidation
Palmitate (16:0) Carbon–carbon cleavage
1 FADH2 + 1 NADH 5 ATP (via electron transport chain)
7 cleavage points x 5 ATP = 35 ATP
Oxidation of acetyl–CoA 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
1st 2nd 3rd 4th 5th 6th last
Special Considerations
Why doesn’t muscle utilize fatty acids during exercise?
Requires oxygen available for oxidation
Use anaerobic fermentation of glucose to lactate preferentially
Why don’t red blood cells utilize fatty acids for their energy metabolism?
No mitochondria in RBC’s
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 H’s to second double bond
Odd Chain Fatty Acids
Minor species, odd chains made by microbes, degradation of AA’s
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
Ketone Bodies (Ketogenesis)
Acetone, acetoacetate, β-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
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
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
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
C18:2, C18:3 Cats cannot synthesize C20:4
Fatty Acid Biosynthesis - Monogastric
Occurs in endoplasmic reticulum
Occurs when:
Energy needs are met (ATP > ADP)
Glycogen stores full
Excess nutrients present
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”
Mitochondria
Cytosol
Acetyl CoA
TCA Cycle Citrate
Citrate
Oxaloacetate
(2C) Acetyl CoA Acetyl CoA Carboxylase (biotin)
HCO3 ATP
(3C) Malonyl CoA
CO2
NADPH
4C Butyryl CoA
2C Acetyl CoA 3C Malonyl CoA
6C Caprayl CoA
CO2
NADPH
Fatty Acid Synthase
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
Fatty Acid Modifications
Palmitate can be elongated
Addition of two-carbon units at COOH-end of fatty acid
Desaturation
C16:0 and C18:0 can be converted to C16:1 and C18:1, respectively
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 (C20:4) from linoleic acid (C18:2)
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
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!!!
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
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 acid–albumin complex
Liver takes up free fatty acids Oxidation or formation of ketone bodies
Leptin
Protein hormone produced by adipocytes
Larger cells = more leptin produced
Effects on many tissues
Hypothalamus
Regulates eating behavior
Negative-feedback mechanism