lipid metabolism

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

Beta Oxidation

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

Summary of β-oxidation

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

Metabolism of natural C20 cis fatty acids produces powerful eicosanoids

Metabolism of Fats

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


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


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)

Lipid Synthesis in Monogastrics

Figure 25.10

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

Groff & Gropper, 1999

Fed state...

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

Leptin-deficient mutants (left) fail to limit their eating and becomes 3

times the weight of normal mouse (right)

lipid metabolism

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