INTEGRATED METABOLISM IN TISSUES

Catabolism of TAGs Oxidation and Synthesis of Fatty Acids

Transfer of Acyl-CoA Ketone Bodies

Catabolism of Cholesterol Essential Fatty Acids

OVERVIEW:

The complete hydrolysis of Triacylglycerols gives us:

a glycerol and three fatty acids.

CATABOLISM OF TAGS AND FATTY

ACIDS

Hydrolysis occurs through:Lipoprotein lipase: non-hepatic tissue

Intracellular lipase: in liver and adipose tissueActivated by epinephrine, norepinephrine,

glucagon and ACTH via cAMPActivated lipase hydrolyzes one fatty acid at a time

HOW DOES THIS HAPPEN?

• Glycerol is used by the liver for energy• Glycerokinase converts glycerol to glycerol

phosphate• Glycerol phosphate can enter the glycolytic

pathway Energy oxidation or Gluconeogenesis

(Adipose tissue cannot metabolize glycerol)

GLYCEROL

*Fatty acids are a rich source of energy

Process:Fatty acids enter cell

Activated by Coenzyme A Acetyl-CoA (using 2 ATP’s)Catalyzed by Acyl-CoA synthetase

Pyrophosphate produced quickly hydrolyzed = irreversible reaction

• Fatty acid oxidation occurs in mitochondrial matrix

• Energy produced through Oxidative Phosphorylation*

• S-C Fatty acids pass directly into mitochondrial matrixAcyl-CoA derivatives

• *L-C Fatty acids and the CoA derivatives cannot

-Carnitine, CAT 1, CAT 2

MITOCHONDRIAL TRANSFER OF ACYL-COA

MITOCHONDRIAL TRANSFER OF ACYL-COA

*Breakdown of fatty acids into acetyl-CoA

• Mitochondrion• *Cyclic Degradative Pathway• *Dehydrogenases

Long fatty acidsShort fatty acids

BETA-OXIDATION OF FATTY ACIDS

1. Dehydrogenation forms a double bond between alpha and beta carbons

2. Hydrogenation to unsaturated acyl-coa3. B-hydroxy group oxidized to ketone by NAD+

4. B-ketoacyl-CoA cleaved resulting in the insertion of CoA and cleavage of B-carbon

• Products are acetyl-CoA that enters Krebs cycle

• And saturated coA-activated fatty acid with 2 fewer carbons that continues the b-

oxidation cycle

BETA OXIDATION

• *Beta-Oxidation not regulated except by TAG lipase

• Even number carbons due to 2 carbon loss at a time

• 16 carbons= 8 Acetyl-CoA molecules produced

• If fatty acid has an uneven # carbons, B12 and Biotin required to oxidize

• Unsaturated fatty acid oxidation

• Each cleavage of saturated carbon-carbon bond 4 ATPs produced

• For each Acetyl-CoA oxidized 10 ATP produced

• The complete B-oxidation of one palmitic acid, including the oxidation of the FADH2 and NADH produced during this cycle yields about 106 molecules of ATP. *

ENERGY PRODUCED

• Another way for Acetyl-CoA to catabolize in liver

• Ketogenesis- ketone bodies formed• Ketone bodies are three chemicals that

are produced as by-products when fatty acids are broken down for energy.

• Only in Mitochondria

FORMATION OF KETONE BODIES*

• Ketone body formation normally very low in blood.

• Situations of accelerated fatty acid oxidation with low-carb intake => very high levels (Starvation, Low-carb diet, or diabetes)*:

• As carb intake diminishes, oxidation of fatty acids accelerates to provide energy through production of TCA substrates (acetyl-CoA)

• *Shift to fat catabolism accumulation of Acetyl-CoA

• Ketosis

CATABOLISM OF CHOLESTEROL

• Cholesterol is not an energy producing nutrient

• Its four ring structure remains intact through catabolism, eliminated through billary system.

• The biliary system creates, transports, stores, and releases bile into the duodenum to help in digestion.

The biliary system includes the gallbladder, bile ducts and certain cells inside the liver, and bile ducts

outside the liver.

CHOLESTEROL

Delivered to the LiverIn the form of

Chylomicron Remnants& LDL-C and HDL-C

(low density lipoprotein cholesterol, high density lipoprotein cholesterol)

2 ways:1. Hydrolyzed by

esterases to free form-secreted directly into

bile canaliculi

2. Converted into bile acids before

entering the bile

*Delivery Excretion

Key Metabolic Changes:• Hydrocarbon Side Chain reduction at

C17• Carboxylic Acid addition on shortened

chain• Hydroxyl group addition to ring system

of molecule

• Effect of these is to enhance water solubility of sterol facilitating its

excretion in the bile• Enterohepatic circulation can return

absorbed bile salts to the liver• *Hypercholesterolemia treated with

removal of bile salts

METABOLIC CHANGESCHOLESTEROL TO BILE ACID

Non Essential Fatty Acids can be synthesized from simple precursors• Assembly of starter molecule• Acetyl-CoA and Malonyl-CoA

Acetyl-CoA + CO2 = Malonyl-CoAOccurs in CytosolCatalyst- Acetyl-CoA carboxylase has biotin

as prosthetic group= “carboxylation”: Incorporates carboxyl group into a compound using ATP

FATTY ACID SYNTHESIS

Production mostly occurs in mitochondria from pyruvate oxidation, oxidation of fatty acids and degradation of some amino acidsSome formed in cytosol through amino acid

catabolism.Fatty acid synthesis localized in cytosol, but acetyl-CoA produced in matrix is unable to

exit through mitochondrial membrane.Acetyl-CoA gets to cytosol by reacting with oxoloacetate to form citrate, which can pass

through inner membrane.Citrate lyase converts the citrate back to

oxaloacetate and acetyl-CoA.

ACETYL-COA PRODUCTION & MOVEMENT TO CYTOSOL

http://www.dnatube.com/video/641/Fatty-Acid-Biosynthesis

MITOCHONDRIAL MATRIX TRANSFER

• Enzymes involved in fatty acid synthesis arrangement.

• In cytosol• *Enzymes: ACP (Acyl Carrier Protein) & CE

(Condensing Enzyme)• Both have free SH group that Acetyl-CoA

and Malonyl- CoA attach to before synthesis can begin

• Acetyl-CoA transferred to ACP, losing its CoA Acetyl-ACP

• Acetyl group then transferred again to SH of CE leaving ACP-SH

• Malonyl group attaches to this molecule, losing it’s CoA

• Now the fatty acid chain can be extended

FATTY ACID SYNTHASE SYSTEM

STARTER MOLECULE

1. Carbonyl carbon of acetyl group to C2 of Malonyl-Acp, lose CO2 with malonyl carboxyl group

2. B-Ketone reduce using NADPH (from PPS)3. Alchohol dehydrated double bond4. Double bond reduced to butyryl-ACP from

NADPH5. Butyryl transferred to CE exposing ACP SH site

to a 2nd malonyl-coa molecule6. The second malonyl-coA condenses with ACP7. Second condensation rxn takes place, with

coupling of butyryl group on the CE to C2 of malonyl-ACP. 6C chain reduced and transferred to CE in a repetition of steps 2-5.

8. The cycle repeats to form a c16 fatty acid (palmitic)

STEPS OF CHAIN ELONGATION

• Humans cannot introduce double bonds beyond D-9 site

• Linoleic and alpha linoleic- Plant products

• Prostaglandins, Thromboxanes and Leukotriene's can be formed from LA (n-6) (favored in the western diet) & ALA (n-3)

*ESSENTIAL FATTY ACIDS

• EFA’s enter Smooth ER for metabolism• LA y-linoleic acid dihomo-Y-linoleic

acid arachidonic acid• ALA Eicosapentaenoic acid (EPA)• N-6 and n-3 fatty acids compete for

enzymes and take the same path, which can affect the conversion of one or the other

• Eicosanoids transferred to membranes in the form of TAGs or phospholipids. Go through further elongation and desaturations in smooth ER, transferred to the peroxisome and undergo B-oxidation to DHA.

EFA’S METABOLISM AND ROLE

• AA, ALA, EPA and DHA containing phospholipids or TAG are incorporated into any of the cell’s membranes or the neutral lipid. AA is predominant in membranes.

• The higher fluidity from unsaturation = better expression of hormone receptors

• Eicosanoids- Important for hormone-receptor binding sites*

Pro-inflammatoryPro-arrythmic

Activate plateletsVasoconstrictors

Anti-inflammatoryAnti-Arrythmic

Inhibits plateletsVasodilators

DHA: nervous system, vision, neuroprotection, successful aging, and

memory.*

Deep-water fish: Herring, Salmon, Tuna

AA EPA AND DHA

AA (N-6) VS. EPA AND DHA (N-3)

Drag picture to placeholder or click icon to add

• Precursors: CoA-activated fatty acids and G-3-P

• De novo,(a Latin expression meaning

"from the beginning,”), major route

• Salvage pathway increases when a deficiency of

essential amino acid methionine

exists.

SYTNHESIS OF TRIACLYGLYCEROLS

Nearly all tissues in body capable of synthesizing cholesterol from acetyl-CoA

Liver = 20% of endogenous synthesis 80% from extrahepatic tissues, intestine

most active 1 g/day endogenously synthesized

Average daily cholesterol intake 300 mg/day, only half is absorbed

Endogenous synthesis 2/3 total cholesterol

SYNTHESIS OF CHOLESTEROL

1. Cytoplasmic sequence by which 3-hydroxy-3-methylutaryl-CoA (HMG-CoA) formed from 3 mol acetyl-CoA

2. Conversion of HMG-CoA to squalene, including rate limtiing step of cholesterol synthesis, in which HMG-CoA reduced to mevalonic Acid by HMG-CoA reductase

3. Formation of cholesterol from squalene

26 STEPS, 3 STAGES

http://www.dnatube.com/video/253/Cholesterol--biosynthesis

CHOLESTEROL SYNTHESIS

• As total body cholesterol increases, the rate of synthesis decreases. ( negative

feedback regulation of HMG-CoA reductase reaction.)

• Suppression of cholesterol synthesis by dietary cholesterol is unique to liver.

• Statins: HMG-CoA inhibitors, block endogenous cholesterol synthesis

CHOLESTEROL INHIBITORS

• The complete hydrolysis of TAGs Glycerol and 3 fatty Acids

• Fatty Acids are a rich source of energy• Long Chain fatty acids cannot cross inner

membrane, require carnitine.• The breakdown of fatty acids into acetyl-CoA “B-

Oxidation”• The synthesis of fatty acids is essentially the reverse

of B-Oxidation• Ketone bodies are produced when fatty acids are

broken down for energy• Ketosis is a result which disrupts the body’s

acid/base balance, Diabetes• Cholesterol is secreted into bile canliculi or

converted to bile acids.• N-6 EFA’s vs. N-3 EFA’s

SUMMARY